Substituted biaryl amides as C5a receptor modulators

ABSTRACT

Substituted biaryl amides of Formula I are provided. Such compounds are ligands that may be used to modulate C5 a  receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological C5 a  receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

This application claims the benefit of Provisional application Ser. No.60/368,462 filed on Mar. 28, 2002.

Considerable experimental evidence implicates increased levels of C5a ina number of autoimmune diseases and inflammatory and related disorders.

Agents that block the binding of C5a to its receptor other agents,including inverse agonists, which modulate signal transductionassociated with C5a-receptor interactions, can inhibit the pathogenicevents, including chemotaxis, associated with anaphylatoxin activitycontributing to such inflammatory and autoimmune conditions.

SUMMARY OF THE INVENTION

The present invention provides substituted biarylamides of Formula I,below. Such compounds are useful as modulators of C5a receptor andpreferably inhibit C5a receptor activation and/or C5a receptor-mediatedsignal transduction.

Thus, in one aspect the invention provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof.

Ar¹ is, in Formula I:

i) optionally substituted phenyl having at least one optionallysubstituted phenyl or optionally substituted heterocyclic substituentattached thereto, or

ii) optionally substituted carbocycle having from 2 to about 4 partiallyunsaturated or aromatic rings, 3 to 8 members in each ring, or

iii) optionally substituted heteroaryl.

R¹ is optionally substituted cycloalkyl, optionally substituted(cycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl, optionallysubstituted (aryl)alkyl, optionally substituted aryl, optionallysubstituted heteroaryl having about 5 to 7 ring atoms and between 1 and3 ring heteroatoms selected from N, O, and S, or optionally substituted(aryl)alkyl, wherein the aryl portion is fused to a 5- to 7-memberedsaturated or partially unsaturated ring that (a) has 0, 1 or 2 ringatoms independently chosen from N, O and S, with remaining ring atomsbeing carbon, and (b) is substituted with from 0 to 2 substituentsindependently chosen from halogen, alkyl and alkoxy.

R² is alkyl, cycloalkyl, (cycloalkyl)alkyl, heteroaryl,(heteroaryl)alkyl, aryl, (aryl)alkyl, indanyl, or tetrahydronapthyl,each of which is optionally substituted, or R² is optionally substitutedphenyl(C₀-C₂alkyl), wherein the phenyl portion is fused to a 5 to 7membered saturated or partially unsaturated ring that (a) has 0, 1 or 2ring atoms independently chosen from N, O and S, with remaining ringatoms being carbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from halogen, alkyl, alkoxy, haloalkyl, andhaloalkoxy.

Within certain aspects, compounds as described above exhibit an IC₅₀value no greater than 1 μM, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nMor 5 nM in a standard C5a receptor-mediated chemotaxis assay,radioligand binding assay, or calcium mobilization assay. Preferred C5areceptors are mammalian receptors that and may either be cloned,recombinantly expressed receptors or naturally expressed receptors. Incertain embodiments the C5a receptors are primate C5a receptors,including human C5a receptors. In certain embodiments, C5a receptormodulators described herein exhibit an affinity for human C5a receptorsthat is higher than for non-primate C5a receptors; for example incertain embodiments compounds of Formula I exhibit 5-fold or 10-foldgreater affinity for human C5a receptors that for most or allnon-primate C5a receptors.

Certain aspects of the invention are directed to compounds of Formula I,above, that bind specifically to C5a receptors, and preferably alsoexhibit an IC₅₀ value no greater than 1 μM, 500 nM, 200 nM, 100 nM, 50nM, 25 nM, 10 nM or 5 nM in a standard C5a receptor-mediated chemotaxisassay, radioligand binding assay, calcium mobilization assay.

The invention further provides, within certain embodiments, compounds ofFormula I, that exhibit less than 5% agonist activity in a GTP bindingassay.

The present invention further provides, within other aspects,pharmaceutical compositions comprising at least one compound or salt asdescribed above (or a prodrug or hydrate thereof) in combination with aphysiologically acceptable carrier or excipient.

The present invention provides, within further aspects, methods fortreating a patient suffering from a condition responsive to C5a receptormodulation (e.g., a human or non-human animal, such as a domesticatedcompanion animal or livestock animal). Such methods generally compriseadministering to the patient a C5a receptor modulatory amount of atleast one compound or salt as described above. For example the inventioncomprises methods for treating a patient in need of anti-inflammatorytreatment or immune treatment with an effective amount of a compound ofthe invention, e.g. an amount of a compound of the invention sufficientto yield a plasma concentration of the compound (or its activemetabolite, if a pro-drug) or high enough to inhibit white blood cell(e.g., neutrophil) chemotaxis in vitro. Treatment of humans,domesticated companion animals (pets) or livestock animals sufferingsuch conditions with an effective amount of a compound of the inventionis contemplated by the invention. For treating non-human animals of anyparticular species, a compound exhibiting high affinity for the C5areceptor of that particular species is preferred.

Within further aspects, methods are provided for inhibiting signaltransduction activity of a cellular C5a receptor, comprising contactinga cell expressing a C5a receptor with an effective amount of at leastone compound or salt as described above. Such contact may occur in vivoor in vitro. In certain embodiments, the signal transduction activityinhibited is calcium conductance. In other embodiments, the signaltransduction activity inhibited is C5a receptor-mediated cellularchemotaxis, and the method comprises contacting mammalian white bloodcells with a C5a receptor modulatory amount of a compound or salt asdescribed above.

Methods are further provided, within other aspects, for inhibitingbinding of C5a to a C5a receptor. Within certain such aspects, theinhibition takes place in vitro. Such methods comprise contacting a C5areceptor with at least one compound or salt as described above, underconditions and in an amount sufficient to detectably inhibit C5a bindingto the receptor. Within other such aspects, the C5a receptor is in apatient. Such methods comprise contacting cells expressing a C5areceptor in a patient with at least one compound or salt as describedabove at a concentration that would be sufficient to detectably inhibitC5a binding to cells expressing a cloned C5a receptor in vitro.

Compounds as described above are also, in certain aspects, labeled witha detectable marker (e.g., radiolabeled or fluorescein conjugated). Theinvention provides methods of using appropriately labeled compounds ofthe invention as probes for localization of receptors, particularly C5areceptors, for example in tissue sections (e.g., via autoradiography) orin vivo (e.g., via positron emission tomography, PET, or single positronemission computed tomography, SPECT, scanning and imaging).

In a separate aspect, the invention provides methods of using compoundsof the invention as positive controls in assays for receptor activity,such as radioligand binding, calcium mobilization, and C5a-mediatedchemotaxis assays.

The present invention further provides packaged pharmaceuticalpreparation, comprising: (a) a pharmaceutical composition as describedherein in a container; and (b) instructions for using the composition totreat one or more conditions responsive to C5a receptor modulation.

In yet another aspect, the invention provides methods of preparing thecompounds disclosed herein, including the intermediates.

These and other aspects of the present invention will become apparentupon reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Chemical Description and Terminology

Compounds of the present invention are generally described usingstandard nomenclature.

The term “substituted biaryl amide,” as used herein, encompasses allcompounds that satisfy one or more of Formulas I, IA, and II-XIV herein,as well as pharmaceutically acceptable salts, prodrugs and hydrates ofsuch compounds.

Certain compounds described herein contain one or more asymmetricelements such as stereogenic centers, stereogenic axes and the like(e.g., asymmetric carbon atoms) so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. For compounds with two or moreasymmetric elements, these compounds can additionally be mixtures ofdiastereomers. Unless otherwise specified all optical isomers andmixtures thereof are encompassed for compounds having asymmetriccenters. In addition, compounds with carbon-carbon double bonds mayoccur in Z- and E- forms, with all isomeric forms of the compounds beingincluded in the present invention unless otherwise specified. Where acompound exists in various tautomeric forms, the invention is notlimited to any one of the specific tautomers, but rather encompasses alltautomeric forms.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample, and without limitation, isotopes of hydrogen include tritiumand deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

Certain compounds are described herein using a general formula, such asFormula I, which includes variables, such as Ar¹, R¹, and R². Unlessotherwise specified, each variable within such a formula is definedindependently of other variables. Thus, for example, if a group is shownto be substituted with 0-2 R*, then said group may optionally besubstituted with up to two R* groups and R* at each occurrence isselected independently from the definition of R*. Also, combinations ofsubstituents and/or variables are permissible only if such combinationsresult in stable compounds.

A “substituent,” as used herein, refers to a molecular moiety that iscovalently bonded to an atom within a molecule of interest. For example,a “ring substituent” may be a moiety such as a halogen, alkyl group,haloalkyl group or other substituent discussed herein that is covalentlybonded to an atom (preferably a carbon or nitrogen atom) that is a ringmember. The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated substituents, provided that the designated atom's normalvalence is not exceeded, and that the substitution results in a stablecompound (i.e., a compound that can be isolated, characterized andtested for biological activity). When a substituent is oxo (i.e., =0),then 2 hydrogens on the atom are replaced. When aromatic moieties aresubstituted by an oxo group, the aromatic ring is replaced by thecorresponding partially unsaturated ring. For example a pyridyl groupsubstituted by oxo is a tetrahydropyridone.

The phrase “optionally substituted” indicates that a group may either beunsubstituted or substituted at one or more of any of the availablepositions, typically 1, 2, 3, 4, or 5 positions, by one or more suitablesubstituents such as those disclosed herein. Various groups within thecompounds and formulae set forth herein are “optionally substituted”including, for example, R¹, R², and Ar¹. Optional substitution may alsobe indicated by the phrase “substituted with from 0 to X substituents,”in which X is the maximum number of substituents.

Suitable substituents include, for example, halogen, cyano, amino,hydroxy, nitro, azido, carboxamido, —COOH, SO₂NH₂, alkyl (e.g.,C₁-C₈alkyl), alkenyl (e.g., C₂-C₈alkenyl), alkynyl (e.g., C₂-C₈alkynyl),alkoxy (e.g., C₁-C₈alkoxy), alkyl ether (e.g., C₂-C₈alkyl ether),alkylthio (e.g., C₁-C₈alkylthio), mono- or di-(C₁-C₈alkyl)amino,haloalkyl (e.g., C₁-C₆haloalkyl), hydroxyalkyl (e.g.,C₁-C₆hydroxyalkyl), aminoalkyl (e.g., C₁-C₆aminoalkyl), haloalkoxy(e.g., C₁-C₆haloalkoxy), alkanoyl (e.g., C₁-C₈alkanoyl), alkanone (e.g.,C₁-C₈alkanone), alkanoyloxy (e.g., C₁-C₈alkanoyloxy), alkoxycarbonyl(e.g., C₁-C₈alkoxycarbonyl), mono- and di-(C₁-C₈alkyl)amino, mono- anddi-(C₁-C₈alkyl)aminoC₁-C₈alkyl, mono- and di-(C₁-C₈alkyl)carboxamido,mono- and di-(C₁-C₈alkyl)sulfonamido, alkylsulfinyl (e.g.,C₁-C₈alkylsulfinyl), alkylsulfonyl (e.g., C₁-C₈alkylsulfonyl), aryl(e.g., phenyl), arylalkyl (e.g., (C₆-C₁₈aryl)C₁-C₈alkyl, such as benzyland phenethyl), aryloxy (e.g., C₆-C₁₈aryloxy such as phenoxy),arylalkoxy (e.g., (C₆-C₁₈aryl)C₁-C₈alkoxy) and/or 3- to 8-memberedheterocyclic groups. Certain groups within the formulas provided hereinare optionally substituted with from 1 to 3, 1 to 4 or 1 to 5independently selected substituents.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, and wherespecified, having the specified number of carbon atoms. Thus, the termC₁-C₆alkyl, as used herein, indicates an alkyl group having from 1 to 6carbon atoms. “C₀-C₄alkyl” refers to a bond or a C₁-C₄alkyl group. Alkylgroups include groups having from 1 to 8 carbon atoms (C₁-C₈alkyl), from1 to 6 carbon atoms (C₁-C₆alkyl) and from 1 to 4 carbon atoms(C₁-C₄alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. “Aminoalkyl” is an alkyl group asdefined herein substituted with one or more —NH₂ groups. “Hydroxyalkyl”is a hydroxy group as defined herein substituted with one or more —OHgroups.

“Alkenyl” refers to a straight or branched hydrocarbon chain comprisingone or more unsaturated carbon-carbon bonds, such as ethenyl andpropenyl. Alkenyl groups include C₂-C₈alkenyl, C₂-C₆alkenyl andC₂-C₄alkenyl groups (which have from 2 to 8, 2 to 6 or 2 to 4 carbonatoms, respectively), such as ethenyl, allyl or isopropenyl.

“Alkynyl” refers to straight or branched hydrocarbon chains comprisingone or more triple carbon-carbon bonds. Alkynyl groups includeC₂-C₈alkynyl, C₂-C₆alkynyl and C₂-C₄alkynyl groups, which have from 2 to8, 2 to 6 or 2 to 4 carbon atoms, respectively. Alkynyl groups includefor example groups such as ethynyl and propynyl.

“Alkoxy” represents an alkyl group as defined above with the indicatednumber of carbon atoms attached through an oxygen bridge. Examples ofalkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy,3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and3-methylpentoxy.

The term “alkanoyl” refers to an acyl group in a linear or branchedarrangement (e.g., —(C═O)-alkyl). Alkanoyl groups include C₂-C₈alkanoyl,C₂-C₆alkanoyl and C₂-C₄alkanoyl groups, which have from 2 to 8, 2 to 6,or 2 to 4 carbon atoms, respectively. “C₁alkanoyl” refers to —(C═O)—H,which (along with C₂-C₈alkanoyl) is encompassed by the term“C₁-C₈alkanoyl.”

The term, “alkyl ether” refers to a linear or branched ether substituentlinked via a carbon-carbon bond. Alkyl ether groups include C₂-C₈alkylether, C₂-C₆alkyl ether and C₂-C₆alkyl ether groups, which have 2 to 8,2 to 6, or 2 to 4 carbon atoms, respectively. By way of example, aC₂alkyl ether group has the structure —CH₂—O—CH₃.

The term “alkoxycarbonyl” refers to an alkoxy group linked via acarbonyl (i.e., a group having the general structure —C(═O)—O-alkyl).Alkoxycarbonyl groups include C₂-C₈, C₂-C₆, and C₂-C₄alkoxycarbonylgroups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms,respectively. “C₁alkoxycarbonyl” refers to —C(═O)OH, and is encompassedby “C₁-C₈alkoxycarbonyl.”

“Alkanoyloxy,” as used herein, refers to an alkanoyl group linked via anoxygen bridge (i.e., a group having the general structure—O—C(═O)-alkyl). Alkanoyloxy groups include C₂-C₈, C₂-C₆, andC₂-C₄alkanoyloxy groups, which have from 2 to 8, 2 to 6, or 2 to 4carbon atoms, respectively.

As used herein, the term “alkylthio” refers to an alkyl group attachedvia a thioether linkage. Alkylthio groups include C₁-C₈alkylthio,C₁-C₆alkylthio and C₁-C₄alkylthio, which have from 1 to 8, 1 to 6 or 1to 4 carbon atoms, respectively.

“Alkylsulfinyl,” as used herein, refers to an alkyl group attached via asulfinyl linkage. Alkylsulfinyl groups include C₁-C₈alkylsulfinyl,C₁-C₆alkylsulfinyl, and C₁-C₄alkylsulfinyl, which have from 1 to 8, 1 to6, and 1 to 4 carbon atoms, respectively.

By “alkylsulfonyl,” as used herein, is meant an alkyl group attached viaa sulfonyl linkage. Alkylsulfonyl groups include C₁-C₈alkylsulfonyl,C₁-C₆alkylsulfonyl, and C₁-C₄alkylsulfonyl, which have from 1 to 8, 1 to6, and 1 to 4 carbon atoms, respectively.

“Alkylamino” refers to a secondary or tertiary amine having the generalstructure —NH— alkyl or —N(alkyl)(alkyl), wherein each alkyl may be thesame or different. Such groups include, for example, mono- anddi-(C₁-C₈alkyl)amino groups, in which each alkyl may be the same ordifferent and may contain from 1 to 8 carbon atoms, as well as mono- anddi-(C₁-C₆alkyl)amino groups and mono- and di-(C₁-C₄alkyl)amino groups.Alkylaminoalkyl refers to an alkylamino group linked via an alkyl group(i.e., a group having the general structure -alkyl-NH-alkyl or-alkyl-N(alkyl)(alkyl)). Such groups include, for example, mono- anddi-(C₁-C₈alkyl)aminoC₁-C₈alkyl, mono- anddi-(C₁-C₆alkyl)aminoC₁-C₆alkyl, and mono- anddi-(C₁-C₄alkyl)aminoC₁-C₄alkyl, in which each alkyl may be the same ordifferent.

The term “carboxamido” or “amido” refers to an amide group (i.e.,—(C═O)NH₂). “Alkylcarboxamido” refers to —NHC(═O)alkyl, preferably—NHC(═O)C₁-C₂alkyl.

The term “cycloalkyl” refers to hydrocarbon ring groups, having thespecified number of carbon atoms, usually from 3 to about 8 ring carbonatoms, or from. Cycloalkyl groups include C₃-C₈, and C₃-C₇ cycloalkylgroups, which have from 3 to 8 and 3 to 7 carbon atoms, respectively.Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl groups, as well as bridged and cagedsaturated ring groups such as norbornane or adamantane and the like.

In the term “(cycloalkyl)alkyl,” “cycloalkyl” and “alkyl” are as definedabove, and the point of attachment is on the alkyl group. This termencompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl,and cyclohexylethyl.

The term “halogen” indicates fluorine, chlorine, bromine, or iodine.

“Haloalkyl” refers to both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with I or more halogen atoms. Examples of haloalkylinclude, but are not limited to, trifluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined above attachedthrough an oxygen bridge.

As used herein, the term “aryl” indicates aromatic groups containingonly carbon in the aromatic ring(s). Such aromatic groups may be furthersubstituted with carbon or non-carbon atoms or groups. Typical arylgroups contain 1 to 3 separate or fused rings, at least one of which isaromatic, and from 6 to about 18 ring atoms, without heteroatoms as ringmembers. Specifically preferred carbocyclic aryl groups include phenyland napthyl, including 1-naphthyl and 2-naphthyl. When indicated, carbonatoms present within a carbocyclic ring may be optionally substitutedwith any of variety of ring substituents, as described above, or withspecifically listed substituents.

The term “arylalkyl” refers to an aryl group is linked via an alkylgroup. Certain arylalkyl groups are (C₆-C₁₈aryl)C₁-C₈alkyl groups (i.e.,groups in which a 6- to 18-membered aryl group is linked via aC₁-C₈alkyl group). Such groups include, for example, groups in whichphenyl or naphthyl is linked via a bond or C₁-C₈alkyl, preferably viaC₁-C₄alkyl, such as benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and2-phenyl-ethyl.

The term “aryloxy” refers to an aryl group linked via a carbonyl (i.e.,a group having the general structure —C(═O)—O-aryl). Phenoxy is arepresentative aryloxy group.

As used herein, the term “heteroaryl” is intended to indicate a stable5- to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclicheterocyclic ring which contains at least 1 aromatic ring that containsfrom 1 to 4 heteroatoms selected from N, O, and S, with remaining ringatoms being carbon. When the total number of S and O atoms in theheteroaryl group exceeds 1, then these heteroatoms are not adjacent toone another. It is preferred that the total number of S and O atoms inthe heterocycle is not more than 1, 2, or 3, more typically 1 or 2. Itis particularly preferred that the total number of S and O atoms in thearomatic heterocycle is not more than 1. Examples of heteroaryl groupsinclude pyridyl, furanyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl,imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl. isoxazolyl,quinolinyl, pyrrolyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline.

The term “heterocyclic group” or “heterocycle” is used to indicatesaturated, partially unsaturated, or aromatic groups having 1 or 2rings, 3 to 8 atoms in each ring and in at least one ring between 1 and3 heteroatoms selected from N, O, and S. Any nitrogen or sulfurheteroatoms may optionally be oxidized. The heterocyclic group may beattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure. The heterocyclic groups described hereinmay be substituted on a carbon or nitrogen atom if the resultingcompound is stable. A nitrogen atom in the heterocycle may optionally bequaternized.

Representative examples of heteroaryl groups and heterocyclic groupsinclude, but are not limited to, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl;- 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, and xanthenyl.

“A C5a receptor” is a G-coupled protein receptor that specifically bindsC5a protein.

Preferably the C5a receptor is a human C5a receptor such as the proteinproduct of the sequence of the resulting PCR product described by Gerardand Gerard, (1991) Nature 349:614-17. The human C5a receptor may also bethat described by Boulay (1991) Biochemistry, 30(12): 2993-9 (GENBANKAccension No. M62505). Non-primate C5a receptors may be a rat C5areceptor such as a rat C5a receptor, GENBANK Accension Nos. X65862,Y09613, and AB003042, a canine C5a receptor, GENBANK Accension No.X65860, or a guinea pig C5a receptor, GENBANK Accension No. U86103.

A “C5a receptor modulator” is any compound that modulates C5a receptoractivation and/or activity (i.e., C5a receptor-mediated signaltransduction, as measured using a C5a receptor-mediated chemotaxis,radioligand binding assay, or calcium mobilization assay as providedherein). In certain embodiments, such a modulator may be exhibit anaffinity constant or IC₅₀ for binding to a C5a receptor of less than 1micromolar. In other embodiments the a C5a receptor modulator mayexhibit an affinity constant or IC₅₀ of less than 500 nM, 200 nM, 100nM, 50 nM, 25 nM, 10 nM or 5 nM in a standard C5a receptor-mediatedchemotaxis assay, radioligand binding assay, or calcium mobilizationassay. A modulator may be a C5a receptor agonist or antagonist,although, for certain purposes described herein, a modulator preferablyinhibits C5a activation resulting from binding of C5a (i.e., themodulator is an antagonist). Preferred antagonists exhibit an antagonistIC₅₀ (which is used herein interchangeably with EC₅₀) of less than 1micromolar, preferably less than 100 nanomolar, in an assay of C5areceptor-mediated chemotaxis, radioligand binding, and/or calciummobilization. In addition, or alternatively, a modulator may act as aninverse agonist of C5a receptor. In certain embodiments, modulatorsprovided herein modulate activation and/or activity of a primate C5areceptor, such as human C5a receptor, which may be a cloned,recombinantly expressed receptor or a naturally expressed receptor. Fortreating non-human animals of any particular species, a compoundexhibiting high affinity for the C5a receptor of that particular speciesis preferred.

An “inverse agonist” of the C5a receptor is a compound which inhibitsthe activity of C5a at the C5a receptor, and reduces the activity of theC5a receptor below its basal activity level in the absence of added C5a.Inverse agonists of the C5a receptor may also inhibit binding of C5a tothe C5a receptor. The ability of a compound to inhibit the binding ofC5a to the C5a receptor may be measured by a binding assay, such as theradioligand binding assay given in Example 19. The basal activity of theC5a receptor may be determined from a GTP binding assay, such as theassay of Example 20. The reduction of C5a activity may also bedetermined from a GTP binding assay such as the assay of Example 20 or acalcium mobilization assay such as the assay of Example 21.

A “neutral antagonist of the C5a receptor is a compound which inhibitsthe activity of C5a at the C5a receptor, but does not significantlychange the basal activity of the C5a receptor. Neutral antagonists ofthe C5a receptor may inhibit the binding of C5a to the C5a receptor.

A “partial agonist” of the C5a receptor elevates the activity of the C5areceptor above the basal activity level of the receptor in the absenceof C5a, but does not elevate the activity of the C5a receptor to thelevel brought about by saturating levels of the natural agonist, C5a.Partial agonist compounds may inhibit the binding of C5a to the C5areceptor. Partial agonists of the C5a receptor usually elevate theactive of the C5a receptor from 5% to 90% of the activity level broughtabout by saturated concentrations of the natural agonist, C5a.

A “C5a receptor modulatory amount” of a compound is an amount that issufficient to yield a plasma concentration of the compound (or itsactive metabolite, if a prodrug) high enough to detectably alter(modulate) C5a receptor activity and/or ligand binding, when thatconcentration is used in an in vitro assay. Suitable in vitro assaysinclude the standard in vitro C5a receptor-mediated chemotaxis assay(described in Example 14 herein); C5a receptor-mediated calciummobilization assay (described in Example 21 herein); and/or radioligandbinding assay such as the assay provided in Example 19.

A “therapeutically effective amount” of a compound is an amount that issufficient to result in a discernible patient benefit. For example, atherapeutically effective amount may reduce symptom severity orfrequency. Alternatively, or in addition, a therapeutically effectiveamount may improve patient outcome and/or prevent or delay disease orsymptom onset.

As used herein, a “pharmaceutically acceptable salt” is an acid or basesalt that is generally considered in the art to be suitable for use incontact with the tissues of human beings or animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication. Such salts include mineral and organic acid salts of basicresidues such as amines, as well as alkali or organic salts of acidicresidues such as carboxylic acids. Specific pharmaceutical saltsinclude, but are not limited to, salts of acids such as hydrochloric,phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic,sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic,ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic,2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic,glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic,hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic,HOOC—(CH₂)_(n)—COOH where n is 0-4 and the like. Similarly,pharmaceutically acceptable cations include, but are not limited tosodium, potassium, calcium, aluminum, lithium and ammonium. Those ofordinary skill in the art will recognize further pharmaceuticallyacceptable salts for the compounds provided herein, including thoselisted by Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., p. 1418 (1985). Accordingly, the presentdisclosure should be construed to include all pharmaceuticallyacceptable salts of the compounds specifically recited. A wide varietyof synthetic procedures is available for the preparation ofpharmaceutically acceptable salts. In general, a pharmaceuticallyacceptable salt can be synthesized from a parent compound that containsa basic or acidic moiety by any conventional chemical method. Briefly,such salts can be prepared by reacting the free acid or base forms ofthese compounds with a stoichiometric amount of the appropriate base oracid in water, an organic solvent, or a mixture of the two; generally,nonaqueous media like ether, ethyl acetate, ethanol, isopropanol oracetonitrile are preferred.

A “prodrug” is a compound that may not fully satisfy the structuralrequirements of the compounds provided herein, but is modified in vivo,following administration to a patient, to produce a substituted biarylamide. For example, a prodrug may be an acylated derivative of acompound as provided herein. Prodrugs include compounds wherein hydroxy,amine, or sulfhydryl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to, acetate, formate, and benzoate derivatives ofalcohol and amine functional groups within the compounds providedherein. Preferred prodrugs include acylated derivatives. Prodrugs may beprepared by modifying functional groups present in the compounds in sucha way that the modifications are cleaved to the parent compounds. Thoseof ordinary skill in the art will recognize various synthetic methodsthat may be employed to prepare prodrugs of the compounds providedherein.

A “patient” is any individual treated with a C5a modulator as providedherein. Patients include humans, as well as other animals such ascompanion animals (e.g., dogs and cats) and livestock. Patients may beexperiencing one or more symptoms of a condition responsive to C5anreceptor modulation, or may be free of such symptom(s) (i.e., treatmentmay be prophylactic).

C5a Receptor Modulators

As noted above, the present invention provides C5a receptor modulators(i.e., compounds that modulate C5a receptor-mediated signaltransduction; preferably compounds that also detectably bind to C5areceptor). C5a receptor modulators may be used to modulate C5a receptoractivity in a variety of contexts, including in the treatment ofpatients suffering from diseases or disorders responsive to C5a receptormodulation, such as autoimmune disorders and inflammatory conditions.C5a receptor modulators may also be used within a variety of in vitroassays (e.g., assays for receptor activity), as probes for detection andlocalization of C5a receptor and as standards in assays of ligandbinding and C5a receptor-mediated signal transduction.

C5a receptor modulators provided herein are substituted biaryl amides ofFormula I (as well as pharmaceutically acceptable salts and prodrugsthereof) that detectably alter, preferably decrease, C5a receptoractivation and/or signal transduction activity at submicromolarconcentrations. Such an alteration in C5a receptor activity may bemeasured using a standard in vitro C5a receptor-mediated chemotaxisassay (Example 14), a C5a receptor-mediated calcium mobilization assay(Example 21) and/or a radioligand binding assay (Example 19). Thepresent invention is based, in part, on the discovery that smallmolecules of Formula I act as antagonists and/or inverse agonists of C5areceptors.

Thus, an embodiment of the invention is directed to compounds of FormulaI:

and the pharmaceutically acceptable salts thereof.

Ar¹ is in this embodiment of the invention is

-   -   i) optionally substituted phenyl having at least one optionally        substituted phenyl or optionally substituted heterocyclic        substituent attached thereto, or    -   ii) optionally substituted 9H-fluorenyl, optionally substituted        heteroaryl, or substituted naphthyl.

In certain embodiments it is preferred that Ar¹ is an optionallysubstituted phenyl having at an optionally substituted phenyl oroptionally substituted heterocyclic substituent attached thereto at theortho position or that Ar¹ is an optionally substituted naphthyl grouphaving a substituent at the ortho position.

R¹, in this embodiment, is optionally substituted cycloalkyl, optionallysubstituted (cycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl,optionally substituted (aryl)alkyl, optionally substituted aryl,optionally substituted heteroaryl having about 5 to 7 ring atoms andbetween 1 and 3 ring heteroatoms selected from N, O, and S, oroptionally substituted (aryl)alkyl, wherein the aryl portion is fused toa 5- to 7-membered saturated or partially unsaturated ring that (a) has0, 1 or 2 ring atoms independently chosen from N, O and S, withremaining ring atoms being carbon, and (b) is substituted with from 0 to2 substituents independently chosen from halogen, alkyl and alkoxy.

R², in this embodiment, is alkyl, cycloalkyl, (cycloalkyl)alkyl,heteroaryl, (heteroaryl)alkyl, aryl, (aryl)alkyl, indanyl, ortetrahydronapthyl, each of which is optionally substituted, or R² isoptionally substituted phenyl(C₀-C₂alkyl), wherein the phenyl portion isfused to a 5 to 7 membered saturated or partially unsaturated ring that(a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, withremaining ring atoms being carbon, and (b) is substituted with from 0 to3 substituents independently chosen from halogen, alkyl, alkoxy,haloalkyl, and haloalkoxy.

In certain embodiments the invention includes compounds andpharmaceutically acceptable salts of Formula I wherein: R² is selectedfrom indanyl, (aryl)alkyl, and cycloalkyl, each of which is optionallysubstituted.

The invention also includes compounds and pharmaceutically acceptablesalts of Formula I in which Ar¹ is selected from: i) phenyl having atleast one phenyl substituent or heterocyclic substituent attachedthereto, wherein each phenyl, phenyl substituent, or heterocyclicsubstituent is substituted with from 0 to 4 substituents independentlyselected from halogen, amino, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, mono- and di-C₁-C₄alkylamino, C₁-C₂alkylthio, and —NHC(═O) C₁-C₂ alkyl; ii) naphthyl substituted with from1 to 3 substituents independently selected from halogen, amino, cyano,hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy,mono- and di-C₁-C₄alkylamino, C₁-C₂ alkylthio, —NHC(═O) C₁-C₂ alkyl,optionally substituted phenyl, and optionally substituted thienyl; iii)9H-fluorenyl substituted with from 0 to 3 substituents independentlyselected from halogen, amino, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, mono- and di-C₁-C₄alkylamino, C₁-C₂alkylthio, —NHC(═O) C₁-C₂ alkyl; and iv) heteroaryl substituted withfrom 0 to 3 substituents independently selected from halogen, amino,cyano, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, mono- and di-C₁-C₄alkylamino, C₁-C₂alkylthio, and—NHC(═O) C₁-C₂ alkyl.

R¹, in this embodiment is: i) (heteroaryl)C₀-C₄alkyl or (aryl)C₀-C₄alkyl, each of which is substituted with from 0 to 3 substituentsindependently selected from halogen, hydroxy, nitro, cyano, C₁-C₄ alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkylthio,—NC(═O)C₁-C₂alkyl, mono- and di(C₁-C₂alkyl)amino, C₂-C₃alkanoyloxy,C₁-C₃alkoxycarbonyl, C₁-haloalkyl, C₁-C₂haloalkoxy, thienyl, and phenyl;or ii) (aryl)C₁-C₄alkyl substituted with from 0 to 5 substituentsindependently chosen from halogen, hydroxy, C₁-C₂ alkyl, C₁-C₂ alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, wherein the aryl portion is fusedto a 5- to 7-membered saturated or partially unsaturated ring that (a)has 0, 1 or 2 ring atoms independently chosen from N, O and S, withremaining ring atoms being carbon, and (b) is substituted with from 0 to2 substituents independently chosen from halogen, C₁-C₄alkyl andC₁-C₄alkoxy.

R² is selected from C₃-C₇ cycloalkyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl,(heteroaryl)C₁-C₄alkyl, (aryl)C₁-C₄alkyl, and indanyl; each of which issubstituted with from 0 to 5 substituents independently selected fromhalogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio,—NC(═O)C₁-C₂alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, thienyl, and phenyl.Compounds and salts of this embodiment will be referred to as compoundsof Formula IA.

For certain compounds and salts of Formula IA, R² is selected from: (i)2-indanyl substituted with from 0 to 2 substituents independentlyselected from halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; and (ii)phenyl(C₁-C₂alkyl) substituted with from 0 to 3 substituentsindependently selected from halogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The invention also includes compounds and salts of Formula IA describedby general Formula II:

Ar¹, in Formula II, is i) phenyl substituted with from 0 to 4substituents independently selected from halogen, hydroxy, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₂alkylthio, and—NHC(═O) C₁-C₂ alkyl, and substituted at the 2-position relative to thepoint of attachment with phenyl, thienyl, imidazolyl, pyrrolyl,pyrazolyl, oxazolyl, naphthyl, thiazolyl, or pyrimidinyl, each of whichis substituted with from 0 to 3 substituents independently selected fromhalogen, amino, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono- and di-C₁-C₄alkylamino, C₁-C₂alkylthio, and —NHC(═O) C₁-C₂ alkyl, or ii) naphthyl substituted withfrom 1 to 3 substituents independently selected from (a) halogen, amino,cyano, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono- and di-C₁-C₄alkylamino, C₁-C₂alkylthio, and —NHC(═O)C₁-C₂ alkyl, and (b) phenyl and thienyl, each of which is substitutedwith from 0 to 3 substituents independently chosen from halogen,C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; iii)9H-fluorenyl substituted with from 0 to 3 substituents independentlyselected from halogen, amino, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, C₁-C₂ haloalkoxy, mono- and di-C₁-C₄alkylamino,C₁-C₂alkylthio, and —NHC(═O) C₁-C₂ alkyl; or iv) heteroaryl substitutedwith from 0 to 3 substituents independently selected from halogen,amino, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono- and di-C₁-C₄alkylamino, C₁-C₂alkylthio, and —NHC(═O)C₁-C₂ alkyl.

Ar², in Formula II, is selected from: i) phenyl, ii) naphthyl, iii) aheterocycle having 1 or 2 rings, 3 to 8 atoms in each ring, and 1 to 3heteroatoms independently selected from N, O, and S; and iv) phenylfused to a 5- to 7-membered saturated or partially unsaturated ringhaving 0, 1, or 2 ring atoms independently chosen from N, O, and S, withremaining ring atoms being carbon; wherein each of i), ii), iii), andiv) is substituted with from 0 to 5 substituents independently selectedfrom halogen, hydroxy, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂ haloalkoxy, C₁-C₂ alkylthio, and —NHC(═O) C₁-C₂ alkyl.

R², in Formula II, is selected from C₃-C₇ cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, (heteroaryl)C₁-C₄alkyl, (aryl)C₁-C₄alkyl,and indanyl; each of which is substituted with from 0 to 3 substituentsindependently selected from halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄alkoxy,C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy,thienyl, and phenyl.

R³ and R⁴ are independently selected from hydrogen, C₁-C₄ alkyl,C₂-C₄alkenyl, and C₂-C₄alkynyl.

The invention also includes compounds of Formula IA wherein R¹ is i)phenyl(C₁-C₂alkyl) substituted with from 0 to 5 substituentsindependently selected from halogen, hydroxy, nitro, cyano, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₁-C₄alkylthio —NC(═O)C₁-C₂alkyl, mono- and di(C₁-C₂alkyl)amino,C₂-C₃alkanoyloxy, C₁-C₃alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,thienyl, and phenyl; or ii) (phenyl)C₁-C₄alkyl substituted with from 0to 3 substituents independently chosen from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, wherein thephenyl portion is fused to a 5- to 7-membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 2 substituents independently chosen fromhalogen, C₁-C₂alkyl and C₁-C₂alkoxy.

In other embodiments the invention includes compounds and salts ofFormula IA wherein R¹ is: i) benzyl substituted with from 0 to 5substituents independently selected from halogen, hydroxy, nitro, cyano,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, mono- and di-(C₁-C₂alkyl)amino,C₂-C₃alkanoyloxy, C₁-C₃alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,thienyl, and phenyl; or ii) phenyl-CH₂-substituted with from 0 to 3substituents independently chosen from halogen, hydroxy, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, wherein the phenylportion is fused to a 5- to 7-membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 2 substituents independently chosen fromchloro, fluoro, methyl and methoxy.

The invention includes certain compounds and salts within in thisembodiment in which R² is: i) 2-indanyl substituted with from 0 to 2substituents independently selected from chloro, fluoro, methyl andmethoxy; or ii) benzyl, piperonyl, benzodioxanylmethyl, andbenzofuranylmethyl, each of which is substituted with from 0 to 3substituents independently selected from halogen, hydroxy, C₁-C₂ alkyl,C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The invention includes certain compounds and salts within in thisembodiment in which R² is 2-indanyl, substituted with from 0 to 2substituents independently selected from chloro, fluoro, methyl andmethoxy.

The invention further includes compounds as salts within this embodimentin which R² is benzyl substituted with from 0 to 3 substituentsindependently selected from halogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,thienyl, and phenyl.

In other embodiments the invention in pertains to compounds andpharmaceutically acceptable salts of Formula III:

Ar³, in these embodiments, is phenyl, pyridyl, furanyl, thienyl,imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, naphthyl, thiazolyl, orpyrimidinyl, each of which is substituted with from 0 to 3 substituentsindependently selected from halogen, hydroxy, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂ haloalkyl,C₁-C₂haloalkoxy, C₁-C₂ alkylthio, and —NHC(═O) C₁-C₂ alkyl.

R⁶ represents from 0 to 4 substituents independently selected fromhalogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₂alkylthio, and —NHC(═O) C₁-C₂ alkyl.

R¹ and R² shown in Formula III carry the definitions set forth above forthese variables in Formula I or (in certain embodiments) Formula IA.

In other embodiments the invention includes compounds of Formula III,wherein R² is: i) 2-indanyl, C₃-C₇cycloalkyl, orC₃-C₇cycloalkyl(C₁-C₄alkyl), each of which is substituted with from 0 to2 substituents independently selected from halogen, hydroxy, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; or ii) benzyl,piperonyl, benzodioxanylmethyl, and benzofuranylmethyl, each of which issubstituted with from 0 to 3 substituents independently selected fromhalogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkylthio,—NC(═O)C₁-C₂alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, thienyl, and phenyl.

Other embodiments pertain to compounds and salts of Formula III, whereinR² is: i) 2-indanyl substituted with from 0 to 2 substituentsindependently selected from chloro, fluoro, methyl and methoxy; or ii)benzyl, piperonyl, benzodioxanylmethyl, or benzofuranylmethyl, each ofwhich is substituted with from 0 to 3 substituents independentlyselected from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.

Other embodiments of the invention pertain to compounds of Formula III,wherein R¹ is: i) benzyl substituted with from 0 to 5 substituentsindependently selected from halogen, hydroxy, nitro, cyano, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, mono- and di(C₁-C₂alkyl)amino,C₂-C₃alkanoyloxy, C₁-C₃alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,thienyl, and phenyl; or ii) phenyl-CH₂-substituted with from 0 to 3substituents independently chosen from halogen, hydroxy, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, wherein the phenylportion is fused to a 5- to 7-membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 2 substituents independently chosen fromchloro, fluoro, methyl and methoxy.

The invention includes compounds and salts of Formula III, in which R¹is: (i) benzyl substituted with from 0 to 5 substituents independentlyselected from halogen, hydroxy, nitro, cyano, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkylthio,—NC(═O)C₁-C₂alkyl, mono- and di(C₁-C₂alkyl)amino, C₂-C₃alkanoyloxy,C₁-C₃alkoxycarbonyl, C₁—C₂haloalkyl, C₁-C₂haloalkoxy, thienyl, andphenyl; or (ii) phenyl-CH₂- substituted with from 0 to 3 substituentsindependently chosen from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, wherein the phenyl portion is fusedto a 5- to 7-membered saturated or partially unsaturated ring that (a)has 0, 1 or 2 ring atoms independently chosen from N, O and S, withremaining ring atoms being carbon, and (b) is substituted with from 0 to2 substituents independently chosen from chloro, fluoro, methyl andmethoxy.

Still other embodiments of the invention pertain to compounds and saltsof Formula III, in which R¹ is: (i) benzyl substituted with from 0 to 5substituents independently selected from halogen, hydroxy, nitro, cyano,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, mono- and di(C₁-C₂alkyl)amino,C₂-C₃alkanoyloxy, C₁-C₃alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,thienyl, and phenyl; or (ii) phenyl-CH₂- substituted with from 0 to 3substituents independently chosen from halogen, hydroxy, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, wherein the phenylportion is fused to a 5- to 7-membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 2 substituents independently chosen fromchloro, fluoro, methyl and methoxy.

Further included in the invention are embodiments pertaining tocompounds and salts of Formula III, wherein Ar³ is 2-thienyl or3-thienyl, each of which is substituted with from 0 to 3 substituentsindependently selected from halogen, hydroxy, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, mono- and di-C₁-C₄alkylamino, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₂ alkylthio, and —NHC(═O) C₁-C₂ alkyl.

In certain of these embodiments, R² is further defined as:

(A) i) 2-indanyl, C₃-C₇cycloalkyl, and C₃-C₇cycloalkyl(C₁-C₄alkyl), eachof which is substituted with from 0 to 2 substituents independentlyselected from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy; or ii) benzyl, piperonyl, benzodioxanylmethyl, andbenzofuranylmethyl, each of which is substituted with from 0 to 3substituents independently selected from halogen, hydroxy, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, thienyl, and phenyl; or R² is

(B) R² is defined as benzyl, piperonyl, benzodioxanylmethyl, orbenzofuranylmethyl, each of which is substituted with from 0 to 3substituents independently chosen from halogen, hydroxy, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, C₁-C₂ haloalkyl,C₁-C₂haloalkoxy, thienyl, and phenyl; or R² is

(C) R² is defined as 2-indanyl substituted with from 0 to 2 substituentsindependently chosen from chloro, fluoro, methyl and methoxy.

Additionally in certain embodiments in which R² is defined as (A), (B),or (C) above:

R¹ is: i) benzyl substituted with from 0 to 5 substituents independentlyselected from halogen, hydroxy, nitro, cyano, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkylthio,—NC(═O)C₁-C₂alkyl, mono- and di-(C₁-C₂alkyl)amino, C₂-C₃alkanoyloxy,C₁-C₃alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, thienyl, andphenyl; or ii) (phenyl)C₁-C₄alkyl substituted with from 0 to 3substituents independently chosen from halogen, hydroxy, C₁-C₂ alkyl,C₁-C₂ alkoxy, haloalkyl, and C₁-C₂haloalkoxy, wherein the phenyl portionis fused to a 5- to 7-membered saturated or partially unsaturated ringthat (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S,with remaining ring atoms being carbon, and (b) is substituted with from0 to 2 substituents independently chosen from chloro, fluoro, methyl andmethoxy.

In other embodiments in which R² is defined as (A), (B), or (C) above,R¹ is: (i) benzyl substituted with from 0 to 5 substituentsindependently selected from halogen, hydroxy, nitro, cyano, —COOH,—CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, mono- and di-(C₁-C₂alkyl)amino,C₂-C₃alkanoyloxy, C₁-C₃alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,thienyl, and phenyl; or (ii) phenyl-CH₂- substituted with from 0 to 3substituents independently chosen from halogen, hydroxy, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, wherein the phenylportion is fused to a 5- to 7-membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 2 substituents independently chosen fromchloro, fluoro, methyl and methoxy.

In still other embodiments in which R²is defined as (A), (B), or (C)above:

R¹ is benzyl optionally substituted with from 0 to 3 substituentsindependently selected from halogen, hydroxy, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, mono- ordi(C₁-C₂alkyl)amino, C₁-C₂ haloalkyl, C₁-C₂haloalkoxy, and phenyl.

The invention also pertains to compounds and salts in which R² isdefined as (A), (B), or (C) above wherein R¹ is piperonyl orbenzofuranylmethyl, each of which is substituted with from 0 to 3substituents independently chosen from is chloro, fluoro, methyl, andmethoxy.

In separate embodiments the invention pertains to compounds and salts ofFormula III, wherein Ar³ is phenyl substituted with from 0 to 3substituents independently selected from halogen, hydroxy, amino, cyano,C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-C₁-C₄alkylamino, C₁-C₂ haloalkyl,C₁-C₂ haloalkoxy, C₁-C₂ alkylthio, and —NHC(═O) C₁-C₂ alkyl.

In certain embodiments of this type:

R² is:

(D) i) 2-indanyl, C₃-C₇cycloalkyl, and C₃-C₇cycloalkyl(C₁-C₄alkyl), eachof which is substituted with from 0 to 2 substituents independentlyselected from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy; or ii) benzyl, piperonyl, benzodioxanylmethyl, andbenzofuranylmethyl, each of which is substituted with from 0 to 3substituents independently selected from halogen, hydroxy, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, thienyl, and phenyl; or R² is

(E) benzyl, piperonyl, benzodioxanylmethyl, or benzofuranylmethyl, eachof which is substituted with from 0 to 3 substituents independentlychosen from halogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio,—NC(═O)C₁-C₂alkyl, C₁-C₂ haloalkyl, C₁-C₂haloalkoxy, thienyl and phenyl;or R² is

(F) 2-indanyl substituted with from 0 to 2 substituents independentlychosen from chloro, fluoro, methyl and methoxy.

In still other embodiments of this type in which R² is defined as (D),(E), or (F) above: R¹ is: i) benzyl substituted with from 0 to 5substituents independently selected from halogen, hydroxy, nitro, cyano,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, mono- and di-(C₁-C₂alkyl)amino,C₂-C₃alkanoyloxy, C₁-C₃alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,thienyl, and phenyl; or ii) (phenyl)C₁-C₄alkyl substituted with from 0to 3 substituents independently chosen from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂ alkoxy, haloalkyl, and C₁-C₂haloalkoxy, wherein the phenylportion is fused to a 5- to 7-membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 2 substituents independently chosen fromchloro, fluoro, methyl and methoxy.

Other embodiments of this type in which R² is defined as (D), (E), or(F) above pertain to compounds in which R¹ is (i) benzyl substitutedwith from 0 to 5 substituents independently selected from halogen,hydroxy, nitro, cyano, —COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, mono- anddi-(C₁-C₂alkyl)amino, C₂-C₃alkanoyloxy, C₁-C₃alkoxycarbonyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, thienyl, and phenyl; or (ii)phenyl-CH₂- substituted with from 0 to 3 substituents independentlychosen from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy, wherein the phenyl portion is fused to a 5- to7-membered saturated or partially unsaturated ring that (a) has 0, 1 or2 ring atoms independently chosen from N, O and S, with remaining ringatoms being carbon, and (b) is substituted with from 0 to 2 substituentsindependently chosen from chloro, fluoro, methyl and methoxy.

In certain embodiments of this type wherein R² is defined as (D), (E),or (F); R¹ is benzyl optionally substituted with from 0 to 3substituents independently selected from halogen, hydroxy, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, mono- ordi(C₁-C₂alkyl)amino, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and phenyl.

In still other embodiments of this type the invention includes compoundsand salts wherein R² is defined as (D), (E), or (F); and R¹ is piperonylor benzofuranylmethyl, each of which is substituted with from 0 to 3substituents independently chosen from is chloro, fluoro, methyl, andmethoxy.

In yet another embodiment the invention includes compounds and salts ofFormula IV:

The variables R¹ and R² shown in Formula IV carry the definitions givenin Formula IA.

Z¹, in this embodiment, is carbon or nitrogen; Z², Z³, and eachoccurrence of Z⁴ are independently selected from CR⁷, NR⁸, S, and O suchthat each S or ring atom, if any, is disposed between two CR⁷ groups,and p is an integer ranging from 1 to 2.

R⁶ in Formula IV, represents from 0 to 4 substituents independentlyselected from halogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₂ alkylthio, and —NHC(═O)C₁-C₂ alkyl.

R⁷, in Formula IV, is independently selected at each occurrence fromhydrogen, halogen, hydroxy, amino, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₂-C₆alkenyl, C₂C₆alkynyl,C₃-C₈cycloalkyl, mono- and di-(C₁-C₆alkyl)amino, cyano, nitro, andC₁-C₆alkanoyl.

R⁸, in Formula IV, is independently selected at each occurrence fromhydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, and C₁-C₆alkanoyl.

In certain embodiments the invention pertains to compounds and salts ofFormula IV in which the group:

comprises from 1 to 4 nitrogen ring atoms and is substituted with from 0to 3 substituents independently selected from hydrogen, halogen,hydroxy, amino, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, mono-and di-C₁-C₆alkylamino, and C₁-C₆ alkanoyl; and pis 1 or 2.

Other embodiments of the invention pertain to compounds andpharmaceutically acceptable salts of Formula V:

The variables R¹ and R² shown in Formula V carry the definitions givenin Formula IA.

R⁶ carries the definition given in Formula IV.

In Formula V one of Z² or Z³ is sulfur or oxygen; and R⁹ represents from0 to 3 substituents independently selected from hydrogen, fluoro,chloro, hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₂haloalkyl, andC₁-C₆haloalkoxy.

Additional embodiments of the invention include compounds andpharmaceutically acceptable salts of Formula VI:

The variables R¹ and R² shown in Formula VI carry the definitions givenin Formula IA.

R⁶ carries the definition given in Formula IV.

In Formula VI, Z³ is nitrogen or CR⁹; and R⁹ represents from 0 to 3substituents independently selected from hydrogen, fluoro, chloro,hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₂haloalkyl, and C₁-C₆haloalkoxy.

Additionally the invention includes compounds and pharmaceuticallyacceptable salts of Formulae IV-VI wherein R² is selected from: i)2-indanyl, C₃-C₇cycloalkyl, and C₃-C₇cycloalkyl(C₁-C₄alkyl), each ofwhich is substituted with from 0 to 2 substituents independentlyselected from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy; and ii) benzyl, piperonyl, benzodioxanylmethyl, andbenzofuranylmethyl, each of which is substituted with from 0 to 3substituents independently selected from halogen, hydroxy, C₁-C₄ alkyl,C₁-C₄alkoxy, C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, thienyl and phenyl.

The invention also includes compounds and pharmaceutically acceptablesalts of Formulae IV-VI wherein R² is benzyl, piperonyl,benzodioxanylmethyl, or benzofuranylmethyl, each of which is substitutedwith from 0 to 3 substituents independently chosen from halogen,hydroxy, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, thienyl, and phenyl.

In other embodiments the invention provides compounds andpharmaceutically acceptable salts of Formulae IV-VI wherein R² is2-indanyl substituted with from 0 to 2 substituents independently chosenfrom chloro, fluoro, methyl and methoxy.

The invention further includes compounds and salts of Formulae IV-VI inwhich R¹ is: i) (phenyl)C₁-C₂ alkyl substituted with from 0 to 5substituents independently selected from halogen, hydroxy, nitro, cyano,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl, mono- and di-(C₁-C₂alkyl)amino,C₂-C₃alkanoyloxy, C₁-C₃alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,thienyl, and phenyl; or ii) (phenyl)C₁-C₄alkyl substituted with from 0to 3 substituents independently chosen from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, wherein thephenyl portion is fused to a 5- to 7-membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 2 substituents independently chosen fromchloro, fluoro, methyl and methoxy.

The invention includes compounds and salts of Formulae IV-VI in which R¹is: i) benzyl substituted with from 0 to 5 substituents independentlyselected from halogen, hydroxy, nitro, cyano, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkylthio—NC(═O)C₁-C₂alkyl, mono- and di-(C₁-C₂alkyl)amino, C₂-C₃alkanoyloxy,C₁-C₃alkoxycarbonyl, C₁-C₂ haloalkyl, C₁-C₂haloalkoxy, thienyl, andphenyl; or ii) phenyl-CH₂- substituted with from 0 to 3 substituentsindependently chosen from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, wherein the phenyl portion is fusedto a 5- to 7-membered saturated or partially unsaturated ring that (a)has 0, 1 or 2 ring atoms independently chosen from N, O and S, withremaining ring atoms being carbon, and (b) is substituted with fro 0 to2 substituents independently chosen from chloro, fluoro, methyl andmethoxy.

In certain embodiments the invention pertains to compounds and salts ofFormulae IV-VI in which R¹ is benzyl substituted with from 0 to 3substituents independently selected from halogen, hydroxy, —COOH,—CONH₂,C₁-C₄alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, —NC(═O)C₁-C₂alkyl,mono- and di-(C₁-C₂alkyl)amino, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, andphenyl.

In other embodiments the invention pertains to compounds and salts ofFormulae IV-VI in which R¹ is piperonyl or benzofuranylmethyl, each ofwhich is substituted with from 0 to 2 substituents independently chosenfrom chloro, fluoro, methyl, and methoxy.

Additional embodiments of the invention include compounds andpharmaceutically acceptable salts of Formula VII:

The variables R², R³ and R⁴ shown in Formula VII carry the definitionsgiven in Formula II.

Z¹, in Formula VII, is carbon or nitrogen;

Z², Z³, and each occurrence of Z⁴ are independently selected from CR⁷,NR⁸, S, and O such that each S or O ring atom, if any, is disposedbetween two CR⁷ groups, p is an integer ranging from 1 to 2; R⁷ inFormula VII, is independently selected at each occurrence from hydrogen,halogen, hydroxy, amino, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, mono-anddi-(C₁-C₆alkyl)amino, cyano, nitro, and C₁-C₆alkanoyl; and R⁸ isindependently selected at each occurrence from hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, andC₁-C₆alkanoyl.

R⁶, in Formula VII, represents from 0 to 4 substituents independentlyselected from halogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₂ alkylthio, and —NHC(═O)C₁-C₂ alkyl.

In certain embodiments the invention pertains to compounds of FormulaVII in which Ar² is: i) phenyl; or ii) phenyl fused to a 5- to7-membered saturated or partially unsaturated ring having 0, 1 or 2 ringatoms independently chosen from N, O and S, with the remaining ringatoms being carbon; wherein each of i) and ii) is substituted with from0 to 2 substituents independently selected from halogen, hydroxy, —COOH,—CONH₂, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R² in this embodiment of the invention is i) 2-indanyl substituted withfrom 0 to 2 substituents independently selected from chloro, fluoro,methyl and methoxy; or ii) benzyl, piperonyl, benzodioxanylmethyl, orbenzofuranylmethyl, each of which is substituted with from 0 to 3substituents independently selected from halogen, hydroxy, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R³ and R⁴ in this embodiment are hydrogen.

The group:

is phenyl or thienyl, each of which is substituted with from 0 to 3substituents independently selected from halogen, hydroxy, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R⁶ in this embodiment represents from 0 to 2 substituents independentlyselected from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyland C₁-C₂haloalkoxy.

Embodiments of the invention pertain to compounds and pharmaceuticallyacceptable salts of Formula VIII:

R, in Formula VIII, is (i) halogen, hydroxy, C₁-C₃haloalkyl, orC₁-C₃haloalkoxy, or (ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, mono- or di-(C₁-C₆alkyl)amino, orC₃-C₇cycloalkyl(C₀-C₄alkyl), each of which is substituted with from 0 to4 substituents independently chosen from halogen, hydroxy, amino, oxo,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, andmono- and di(C₁-C₄)alkylamino, (iii) phenyl, or (iv) a heterocyclicring, having from 4 to 8 ring atoms, and 1 to 3 heteroatomsindependently selected from N, O, and S; wherein each of (iii) and (iv)is substituted with from 0 to 3 substituents independently chosen fromhydroxy, halogen, amino, cyano, nitro, C₁-C₆alkyl, C₁-C₆alkoxy, mono-and di-C₁-C₆alkylamino, mono- and di-C₁-C₆alkylaminoC₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₂ alkylthio, and —NHC(═O)C₁-C₂alkyl.

R², in Formula VIII, is C₃-C₇ cycloalkyl, (C₃-C₇cycloalkyl)C₁-C₄alkyl,(heteroaryl)C₀-C₂alkyl, (aryl)C₀-C₂alkyl, or indanyl; each of which issubstituted with from 0 to 3 groups independently selected from halogen,hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, COOH,—NC(═O)C₁-C₂alkyl, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy; or R² is(phenyl)C₀-C₂alkyl, wherein the phenyl portion is fused to a 5 to 7membered saturated or partially unsaturated ring that (a) has 0, 1 or 2ring atoms independently chosen from N, O and S, with remaining ringatoms being carbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from halogen, hydroxy, cyano, amino, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy.

R³ and R⁴ are independently hydrogen, methyl, or ethyl.

R⁵ and R⁶ each represent 0 or more substituents independently chosenfrom halogen, hydroxy, cyano, nitro, amino, C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆alkynyl, C₁-C₆alkoxy, mono- and di-(C₁-C₆)alkylamino,C₁-C₃haloalkyl, C₁-C₃haloalkoxy, C₁-C₂alkylthio, and —NHC(═O)C₁-C₂alkyl.

Ar² represents i) phenyl ii) naphthyl iii) a heterocycle having 1 or 2rings, 3 to 8 atoms in each ring, and 1 to 3 heteroatoms independentlyselected from N, O, and S; or iv) phenyl fused to a 5- to 7-memberedsaturated or partially unsaturated ring having 0, 1, or 2 ring atomsindependently chosen from N, O, and S, with remaining ring atoms beingcarbon; wherein each of i), ii), iii), and iv) is substituted with from0 to 5 substituents independently selected from a) halogen, hydroxy,cyano, amino, —COOH, —CONH₂, C₁-C₃haloalkyl, and C₁-C₃haloalkoxy, b)C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, mono- anddi-(C₁-C₆alkyl)amino, and (C₃-C₇cycloalkyl)C₀-C₄alkyl, each of which issubstituted with from 0 to 5 substituents independently chosen fromhalogen, hydroxy, amino, oxo, cyano, —COOH, C₁-C₄alkyl, C₁-C₄alkoxy,mono- and di(C₁-C₄)alkylamino, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₄alkylcarboxamide, C₁-C₄alkylsufinyl, C₁-C₄alkylsufonyl,C₁-C₄alkylsufonate, C₂-C₄alkylester, and C₁-C₄alkoxycarbonyl, c)C₁-C₄alkylcarboxamide, C₁-C₄alkanoyl, C₁-C₄alkylsufinyl,C₁-C₄alkylsufonyl, C₁-C₄alkylsufonate, C₂-C₄alkylester,C₁-C₄alkoxycarbonyl, and heterocycloalkyl(C₀-C₄alkyl), and d)(heterocycle)C₀-C₄alkyl, having 1 or 2 rings, 3 to 8 atoms in each ring,and 1 to 3 heteroatoms independently selected from N, O, and S,substituted with from 0 to 3 groups independently chosen from halogen,hydroxy, nitro, amino, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂ haloalkyl, C₁-C₂haloalkoxy, and 5- to 7- membered heterocycloalkyl substituents.

In certain other embodiments the invention pertains to compounds andsalts of Formula VIII in which R³, R⁴, R⁵, and R⁶ carry the values givenfor these variables in Formula VIII.

R is chosen from (i) halogen, hydroxy, C₁-C₃haloalkyl, andC₁-C₃haloalkoxy, (ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkyl₁O—, C₁-C₆alkoxy, mono- or di-(C₁-C₆alkylamino, orC₃-C₇cycloalkyl(C₀-C₄alkyl), each of which is substituted with from 0 to4 substituents independently chosen from halogen, hydroxy, amino, oxo,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, andmono- and di-(C₁-C₄alkyl)amino, (iii) phenyl, and (iv) pyridinyl,pyrimidinyl, pyrazinyl, thienyl, imidazolyl, pyrazolyl, pyrrolyl,furanyl, oxazolyl, thiazolyl, isoxazolyl, pyrrolidinyl, morpholinyl,piperazinyl, and piperidinyl, wherein each of (iii) and (iv) issubstituted with from 0 to 3 substituents independently chosen fromhydroxy, halogen, amino, cyano, nitro, C₁-C₆alkyl, C₁-C₆alkoxy, mono-and di-C₁-C₆alkylamino, mono- and di-C₁-C₆alkylaminoC₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, C₁-C₂ alkylthio, and—NHC(═O)C₁-C₂alkyl.

R², in this embodiment, is C₃-C₇ cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, pyridylmethyl, pyrimidinylmethyl,pyrazinylmethyl, thienylmethyl, quinazolinylmethyl,benzothiazolylmethyl, indolylmethyl, benzimidazolylmethyl, phenyl,benzyl, phenthyl, or indanyl; each of which is substituted with from 0to 3 groups independently selected from halogen, hydroxy, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄alkylthio, —COOH, —NC(═O)C₁-C₂alkyl, C₁-C₂ haloalkyl,and C₁-C₂haloalkoxy; or R² is benzyl fused to a 5 to 7 memberedsaturated or partially unsaturated ring that (a) has 0, 1 or 2 ringatoms independently chosen from N, O and S, with remaining ring atomsbeing carbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from halogen, hydroxy, cyano, amino, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy.

Ar² represents i) phenyl, ii) naphthyl, iii) pyridyl, pyrimidinyl,pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl, orbenzimidazolyl) phenyl fused to a 5 to 7 membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, wherein each ofi), ii), iii), and iv) is substituted with from 0 to 5 groupsindependently selected from a) halogen, hydroxy, cyano, amino, —COOH,—CONH₂, C₁-C₃haloalkyl, and C₁-C₃haloalkoxy, b) C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, mono- and di-(C₁-C₆alkyl)amino,and (C₃-C₇cycloalkyl)C₀-C₄alkyl, each of which is substituted with from0 to 5 substituents independently chosen from halogen, hydroxy, amino,oxo, cyano, —COOH, C₁-C₄alkyl, C₁-C₄alkoxy, mono- anddi-(C₁-C₄)alkylamino, C₁-C₂haloalkyl, C₁-C₂haloalkoxyC₁-C₄alkylcarboxamide, C₁-C₄alkylsufinyl, C₁-C₄alkylsufonyl,C₁-C₄alkylsufonate, C₂-C₄alkylester, and C₁-C₄alkoxycarbonyl, and c)C₁-C₄alkylcarboxamide, C₁-C₄alkanoyl, C₁-C₄alkylsufinyl,C₁-C₄alkylsufonyl, C₁-C₄alkylsufonate, C₂-C₄alkylester,C₁-C₄alkoxycarbonyl, and d) (pyrrolidinyl)C₀-C₄alkyl,(morpholinyl)C₀-C₄alkyl, (thiomorpholinyl)C₀-C₄alkyl,(piperazinyl)C₀-C₄alkyl, and (piperidinyl)C₀-C₄alkyl, and(thiazolyl)C₀-C₄alkyl, (piperidyl)C₀-C₄alkyl, (morpholinyl)C₀-C₄alkyl,(pyrrolidinyl)C₀-C₄alkyl, (piperidinyl)C₀-C₄alkyl, and(piperazinyl)C₀-C₄alkyl, each of which is substituted with from 0 to 3groups independently chosen from halogen, hydroxy, nitro, amino,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy,pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, andpiperidinyl.

Still other embodiments of the invention pertain to compounds and saltsof Formula IX:

The variables Ar², R, R³, R⁴ R⁵, and R⁶ carry the definitions set forthabove for Formula VIII.

R⁷ represents from 0 to 3 substituents independently selected fromhalogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl,C₁-C₂haloalkoxy, and mono- and di-(C₁-C₂alkyl)amino.

In certain embodiments the invention includes compounds and salts ofFormula IX in which R⁵ and R⁶ are independently chosen from halogen,cyano, nitro, amino, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, and mono- and di-(C₁-C₂alkyl)amino.

The invention also pertains to compounds and salts of Formula IX inwhich R is chosen from (A) (i) halogen and hydroxy, and (ii) C₁-C₆alkyland C₁-C₆alkoxy each of which is substituted with from 0 to 4substituents independently chosen from halogen, hydroxy, amino, oxo,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, andmono- and di-(C_(1C) ₁-C₄alkyl)amino, or in other embodiments (B) R isC₁-C₂alkyl or C₁-C₂alkoxy, or in still other embodiments (C) R isphenyl, thienyl, or pyridyl, each of which is substituted with from 0 to3 substituents independently chosen from hydroxy, halogen, amino, cyano,nitro, C₁-C₂alkyl, C₁-C₂ alkoxy, C₁-C₂alkylamino,(C₁-C₂alkylamino)C₁-C₂alkyl, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The invention also includes compounds and salts of Formula IX in which Ris defined as (A), (B), or (C) above and Ar² is phenyl substituted withfrom 0 to 5 groups independently selected from halogen, hydroxy, cyano,amino, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₂alkylthio, (C₃-C₇cycloalkyl)C₀-C₂alkyl, and 5- to7-membered heterocycloalkyl groups containing 1, 2, or 3 heteroatomsindependently selected from N, O, and S.

In other embodiments the invention includes compounds and salts ofFormula IX in which R is defined as (A), (B), or (C) above in which Ar²is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, thienyl,quinazolinyl, benzothiazolyl, indolyl, or benzimidazolyl, each of whichis substituted with from 0 to 5 groups independently selected fromhalogen, hydroxy, cyano, amino, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₂alkylthio,C₃-C₇cycloalkyl)C₀-C₂alkyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,piperazinyl, and piperidinyl.

In still other embodiments the invention also includes compounds andsalts of Formula IX in which R is defined as (A), (B), or (C) above inwhich Ar² is phenyl fused to a 5 to 7 membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 3 substituents independently chosen fromhalogen, hydroxy, cyano, amino, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.

The invention includes a particular class of compounds of Formula IX inwhich R² is benzyl or phenethyl, each of which is substituted with from0 to 3 groups independently selected from halogen, hydroxy, C₁-C₄ alkyl,C₁-C₄alkoxy, C₁-C₄alkylthio, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R₅ and R₆, in certain embodiments of this type, are independently chosenfrom halogen, cyano, nitro, amino, C₁-C₂alkyl, C₁-C₂alkoxy, mono- anddi-(C₁-C₂alkyl)amino, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R, in still other embodiments of this type, is chosen from (D) (i)halogen and hydroxy, and (ii) C₁-C₆alkyl and C₁-C₆alkoxy, each of whichis substituted with from 0 to 4 substituents independently chosen fromhalogen, hydroxy, amino, oxo, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and mono- and di-(C₁-C₄alkyl)amino, (E)R is C₁-C₂alkyl or C₁-C₂alkoxy, and (F) R is phenyl, thienyl, orpyridyl, each of which is substituted with from 0 to 3 substituentsindependently chosen from hydroxy, halogen, amino, cyano, nitro,C₁-C₂alkyl, C₁-C₂ alkoxy, C₁-C₂alkylamino, (C₁-C₂alkylamino)C₁-C₂alkyl,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The invention also includes compounds and salts of Formula IX in which Ris defined as (D), (E), or (F) above in which Ar² is phenyl, pyridyl,pyrimidinyl, pyrazinyl, pyrazolyl, thienyl, quinazolinyl,benzothiazolyl, indolyl, or benzimidazolyl, each of which is substitutedwith from 0 to 5 groups independently selected from halogen, hydroxy,cyano, amino, —COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂ haloalkyl,C₁-C₂ haloalkoxy, C₁-C₂ alkylthio, (C₃-C₇cycloalkyl)C₀-C₂alkyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, andpiperidinyl.

The further pertains to compounds and salts of Formula IX in which R isdefined as (D), (E), or (F) above in which Ar² is phenyl fused to a 5 to7 membered saturated or partially unsaturated ring that (a) has 0, 1 or2 ring atoms independently chosen from N, O and S, with remaining ringatoms being carbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from halogen, hydroxy, cyano, amino, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy.

In still other embodiments the invention pertains to compounds and saltsof Formula IX in which R is defined as (D), (E), or (F) above in whichR² is benzyl fused to a 5 to 7 membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 3 substituents independently chosen fromhalogen, hydroxy, cyano, amino, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂ haloalkoxy.

In certain embodiments of this type, R₅ and R₆ are independently chosenfrom halogen, cyano, nitro, amino, C₁-C₂alkyl, C₁-C₂alkoxy, mono- anddi-(C₁-C₂alkyl)amino, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The invention also pertains to compounds and salts of Formula IX inwhich R is defined as (D), (E), or (F) above, and the variables Ar², R,R³, R⁴ R⁵, R⁶ carry the definitions set forth above for Formula VIII.

In certain embodiments of this type Ar² is phenyl fused to a 5 to 7membered saturated or partially unsaturated ring that (a) has 0, 1 or 2ring atoms independently chosen from N, O and S, with remaining ringatoms being carbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from halogen, hydroxy, cyano, amino, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy.

The invention pertains to compounds and salts of Formula II in which Ar¹is heteroaryl substituted substituted with from 0 to 3 substituentsindependently selected from halogen, amino, cyano, hydroxy, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, mono- anddi-C₁-C₄alkylamino, C₁-C₂ alkylthio, —NHC(═O) C₁-C₂ alkyl. For example,the invention pertains to compounds and salts of Formula II in which Ar¹is indolyl or indazolyl, each of which is substituted with from 0 to 3substituents independently selected from halogen, amino, cyano, hydroxy,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, mono- anddi-C₁-C₄alkylamino.

Thus the invention pertains to compounds and salts of Formula II inwhich Formulae X and XI (which fall within the scope of Formula II):

where R⁵ in Formulae X and XI represents from 0 to 3 substituentspresent on either ring of the bicyclic heteroaryl group independentlyselected from halogen, amino, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, mono- and di-C₁-C₄alkylamino, C₁-C₂alkylthio, —NHC(═O) C₁-C₂ alkyl.

R³ and R⁴, in certain embodiments of this type are independently chosenfrom hydrogen, methyl, and ethyl.

Ar², for embodiments of this type, is (A) phenyl substituted with from 0to 5 groups independently selected from halogen, hydroxy, cyano, amino,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₂alkylthio, (C₃-C₇cycloalkyl)C₀-C₂alkyl, and 5-to 7-memberedheterocycloalkyl groups containing 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; or (B) phenyl, pyridyl, pyrimidinyl,pyrazinyl, pyrazolyl, thienyl, quinazolinyl, benzothiazolyl, indolyl, orbenzimidazolyl, each of which is substituted with from 0 to 5 groupsindependently selected from halogen, hydroxy, cyano, amino, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₂ alkylthio,(C₃-C₇cycloalkyl)C₀-C₂alkyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,piperazinyl, and piperidinyl; or Ar² is (C) phenyl fused to a 5 to 7membered saturated or partially unsaturated ring that (a) has 0, 1 or 2ring atoms independently chosen from N, O and S, with remaining ringatoms being carbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from halogen, hydroxy, cyano, amino, C₁-C₂alkyl,C₁-C₂alkoxy, C₁-C₂ haloalkyl, and C₁-C₂haloalkoxy.

In certain of these embodiments Ar² carrries the definition given in(A), (B), or (C) immediately above and R² is i) 2-indanyl substitutedwith from 0 to 2 substituents independently selected from chloro,fluoro, methyl and methoxy; or ii) benzyl, piperonyl,benzodioxanylmethyl, and benzofuranylmethyl, each of which issubstituted with from 0 to 3 substituents independently selected fromhalogen, hydroxy, C₁-C₂ alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.

In other embodiment of this type, Ar² carrries the definition given in(A), (B), or (C) immediately above and R² is 2-indanyl, substituted withfrom 0 to 2 substituents independently selected from chloro, fluoro,methyl and methoxy.

In still other embodiments within this class Ar² carrries the definitiongiven in (A), (B), or (C) immediately above, and R² is benzylsubstituted with from 0 to 3 substituents independently selected fromhalogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkylthio,—NC(═O)C₁-C₂alkyl, C_(1-C) ₂haloalkyl, C₁-C₂haloalkoxy, thienyl, andphenyl.

The invention further pertains to compounds and pharmaceuticallyacceptable salts of Formula II in which Ar¹ is tetrahydronapthyl.

For example the invention pertains to compounds and salts of FormulaXII:

wherein, the variables R², R³, R⁴, and Ar² carry the definitions setforth above for compounds of Formula II and R⁵ in Formula XII representsfrom 0 to 3 substituents present on either ring of the bicyclicheteroaryl group independently selected from halogen, amino, cyano,hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy,mono- and di-C₁-C₄alkylamino, C₁-C₂ alkylthio, —NHC(═O) C₁-C₂ alkyl.

The invention particularly pertains to compounds and salts of FormulaXIII and XIV:

where R⁶ represents from 0 to 3 substituents present on either ring ofthe indanyl group independently selected from halogen, amino,C₁-C₂alkyl, and C₁-C₂alkoxy.

Specific embodiments of the invention include compounds of Formulae XIIIand XIV in which R⁵ represents from 0 to 3 substituents present oneither ring of indanyl group independently selected from halogen,C₁-C₂alkyl, and C₁-C₂alkoxy, R⁶, if present, is methyl, R³ and R⁴ areindependently hydrogen, methyl, or ethyl, and

Ar², for embodiments of this type, is (D) phenyl substituted with from 0to 3 groups independently selected from halogen, hydroxy, cyano, amino,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy; or Ar² is (E) phenyl fused to a 5 to 7 memberedsaturated or partially unsaturated ring that (a) has 0, 1 or 2 ringatoms independently chosen from N, O and S, with remaining ring atomsbeing carbon, and (b) is substituted with from 0 to 3 substituentsindependently chosen from halogen, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; or (F) Ar² is naphthyl ortetrahydronapthyl, each of which may be substituted with from 0 to 4substituents independently chosen from halogen, hydroxy, amino,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; or (G) Ar²is a group of the Formula:

in which G is nitrogen or oxygen and R¹⁰ represents from 0 to 3substituents present on either ring of two ring system independentlyselected from halogen, amino, C₁-C₂alkyl, and C₁-C₂alkoxy.

In other embodiments the invention pertains to compounds and salts ofFormulae XIII and XIV in which R³ and R⁴ are combined to form an oxogroup.

Representative substituted biaryl amides provided herein include, butare not limited to, those specifically described in Examples 1-10. Itwill be apparent that the specific compounds recited therein arerepresentative only, and are not intended to limit the scope of thepresent invention. Further, as noted above, all compounds of the presentinvention may be present as a hydrate, free base or a pharmaceuticallyacceptable acid addition salt.

Certain substituted biaryl amides according to Formulae I, IA, II-XIVhave one or more stereogenic centers. In certain embodiment thereof,such compounds may be enantiomers, and may have an enantiomeric excessof at least 55%. Within further embodiments thereof, such compounds havean enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, 98%, or99%. Certain compounds having one or more stereogenic centers have aenantiomeric excess of at least 99%.

Certain substituted biaryl amides according to Formulae I, IA, andII-XIV have two or more stereogenic centers. In certain embodimentsthereof, such compounds have a diastereomeric excess of at least 55%. Inother embodiments thereof such compounds have a diastereomeric excess of60%, 70%, 80%, 85%, 90%, 95%, or 98%. Certain compounds having two ormore stereogenic centers have a diastereomeric excess of at least 99%.

Substituted biaryl amides provided herein detectably alter (modulate)C5a receptor activity and/or ligand binding, as determined using astandard in vitro C5 receptor-mediated chemotaxis assay (described inExample 14), radioligand binding (described in Example 19), or C5areceptor-mediated calcium mobilization assay (described in Example 21).Preferred compounds exhibit an IC₅₀ of about 500 nM or less in such astandard C5a receptor-mediated chemotaxis, radioligand binding, and/orcalcium mobilization assay, more preferably an IC₅₀ of about 250 nM orless in such an assay, still more preferably an IC₅₀ of about 200, 150,100, 50, 25, 10, or 5 nM or less in such an assay.

Initial characterization of compounds can be conveniently carried outusing a C5a receptor binding assay or functional assay, such as setforth in the Examples, and may be expedited by applying such assays in ahigh throughput screening setting. Additional assays suitable fordetermining the effects of small molecule compounds on C5a receptorbinding and receptor modulatory activity, as well as assays suitable formeasuring their effects on C5a-induced neutropenia in vivo, can be foundin the published literature, for example in U.S. Pat. No. 5,807,824,which is incorporated herein by reference for its disclosure in thisregard in Examples 6-9, columns 19-23, as well as for its discussion ofcomplement and inflammation at columns 1-2. Those of skill in the artwill recognize that such assays can be readily adapted to the use ofcells or animals of different species as deemed appropriate.

In certain embodiments, preferred compounds have favorablepharmacological properties, including oral bioavailability (such that asub-lethal or preferably a pharmaceutically acceptable oral dose,preferably less than 2 grams, more preferably of less than or equal toone gram, can provide a detectable in vivo effect such as a reduction ofC5a-induced neutropenia), ability to inhibit leukocyte chemotaxis atnanomolar concentrations and preferably at sub-nanomolar concentrations,low toxicity (a preferred compound is nontoxic when a C5areceptor-modulatory amount is administered to a subject), minimal sideeffects (a preferred compound produces side effects comparable toplacebo when a C5a receptor-modulatory amount of the compound isadministered to a subject), low serum protein binding, and a suitable invitro and in vivo half-life (a preferred compound exhibits an in vitrohalf-life that is equal to an in vivo half-life allowing for Q.I.D.dosing, preferably T.I.D. dosing, more preferably B.I.D. dosing, andmost preferably once-a-day dosing). Distribution in the body to sites ofcomplement activity is also desirable (e.g., compounds used to treat CNSdisorders will preferably penetrate the blood brain barrier, while lowbrain levels of compounds used to treat periphereal disorders aretypically preferred).

Routine assays that are well known in the art may be used to assessthese properties, and identify superior compounds for a particular use.For example, assays used to predict bioavailability include transportacross human intestinal cell monolayers, such as Caco-2 cell monolayers.Penetration of the blood brain barrier of a compound in humans may bepredicted from the brain levels of the compound in laboratory animalsgiven the compound (e.g., intravenously). Serum protein binding may bepredicted from albumin binding assays, such as those described byOravcová, et al. (1996) Journal of Chromatography B 677:1-27. Compoundhalf-life is inversely proportional to the frequency of dosage of acompound required to achieve an effective amount. In vitro half-lives ofcompounds may be predicted from assays of microsomal half-life asdescribed by Kuhnz and Gieschen (1998) Drug Metabolism and Disposition26:1120-27.

Toxicity and side effects may be assessed using any standard method. Ingeneral, the term “nontoxic” as used herein shall be understood in arelative sense and is intended to refer to any substance that has beenapproved by the United States Food and Drug Administration (“FDA”) foradministration to mammals (preferably humans) or, in keeping withestablished criteria, is susceptible to approval by the FDA foradministration to mammals (preferably humans). Toxicity may be alsoevaluated using the assay detecting an effect on cellular ATPproduction. Other assays that may be used include bacterial reversemutation assays, such as an Ames test, as well as standardteratogenicity and tumorogenicity assays. Preferably, administration ofcompounds provided herein at certain doses (i.e., doses yieldingeffective in vivo concentrations) does not result in prolongation ofheart QT intervals (i.e., as determined by electrocardiography in guineapigs, minipigs or dogs). When administered daily for five or preferablyten days, such doses also do not cause liver enlargement resulting in anincrease of liver to body weight ratio of more than 100%, preferably notmore than 75%, and more preferably not more than 50% over matchedcontrols in laboratory rodents (e.g., mice or rats). Such doses alsopreferably do not cause liver enlargement resulting in an increase ofliver to body weight ratio of more than 50%, preferably not more than25%, and more preferably not more than 10% over matched untreatedcontrols in dogs or other non-rodent mammals.

Certain preferred compounds also do not promote substantial release ofliver enzymes (e.g., ALT, LDH or AST) from hepatocytes in vivo.Preferably the above doses do not elevate serum levels of such enzymesby more than 100%, preferably not by more than 75%, and more preferablynot by more than 50% over matched untreated controls in vivo inlaboratory rodents. Similarly, concentrations (in culture media or othersuch solutions that are contacted and incubated with cells in vitro)equivalent to two-fold, preferably five-fold, and most preferablyten-fold the minimum in vivo therapeutic concentration do not causedetectable release of any of such liver enzymes from hepatocytes invitro into culture medium above baseline levels seen in media fromuntreated cells.

In certain embodiments, preferred compounds exert theirreceptor-modulatory effects with high specificity. This means that theyonly bind to, activate, or inhibit the activity of certain receptorsother than C5a receptors with affinity constants of greater than 100nanomolar, preferably greater than 1 micromolar, more preferably greaterthan 4 micromolar. The invention also includes highly specific C5areceptor modulatory compounds that exhibit 200-fold greater affinity forthe C5a receptor that for other cellular receptors. Such receptorsinclude neurotransmitter receptors such as alpha- or beta-adrenergicreceptors, muscarinic receptors (particularly m1, m2 or m3 receptors),dopamine receptors, and metabotropic glutamate receptors; as well ashistamine receptors and cytokine receptors (e.g., interleukin receptors,particularly IL-8 receptors). Such receptors may also include GABA_(A)receptors, bioactive peptide receptors (other than C5a receptors and C3areceptors, including NPY or VIP receptors), neurokinin receptors,bradykinin receptors, and hormone receptors (e.g., CRF receptors,thyrotropin releasing hormone receptors or melanin-concentrating hormonereceptors). Compounds that act with high specificity generally exhibitfewer undesirable side effects.

Within certain embodiments, modulators provided herein do not binddetectably to receptors that do not mediate inflammatory responses, suchas GABA receptors, MCH receptors, NPY receptors, dopamine receptors,serotonin receptors and VR1 receptors, with high or even moderateaffinity. In addition, or alternatively, certain preferred C5a receptormodulators exhibit an affinity for C5a receptor that is substantiallyhigher than for receptors that do not mediate inflammatory responses(e.g., at least five times higher, at least ten times higher or at least100 times higher). Assays for evaluating binding to receptors that donot mediate inflammatory responses include, for example, those describedin U.S. Pat. No. 6,310,212, which is incorporated herein by referencefor its disclosure of a GABA_(A) receptor binding assays in Examples 14,columns 16-17, in U.S. patent application Ser. No. 10/152,189 which isincorporated herein by reference for its disclosure of an MCH receptorbinding assay in Example 2, pages 104-105, in U.S. Pat. No. 6,362,186,which is incorporated herein by reference for its disclosure of CRF1 andNPY receptor binding assays in Examples 19, columns 45-46, in U.S. Pat.No. 6,355,644, which is incorporated herein by reference for itsdisclosure of a dopamine receptor binding assay at column 10, and inU.S. Pat. No. 6,482,611, which is incorporated herein by reference forits disclosure of VR1 receptor binding assays in Examples 4-5, column14. It will be apparent that the C5a receptor modulators provided hereinmay, but need not, bind to one or more other receptors known to mediateinflammatory responses, such as C3a receptors and/or A₃ receptors.

Certain preferred compounds are C5a receptor antagonists that do notpossess significant (e.g., greater than 5%) agonist activity in any ofthe C5a receptor-mediated functional assays discussed herein.Specifically, this undesired agonist activity can be evaluated, forexample, in the GTP binding assay of Example 20, by measuring smallmolecule mediated GTP binding in the absence of the natural agonist,C5a. Similarly, in a calcium mobilization assay (e.g., that of Example21) a small molecule compound can be directly assayed for the ability ofthe compound to stimulate calcium levels in the absence of the naturalagonist, C5a. The preferred extent of C5a agonist activity exhibited bycompounds provided herein is less than 10%, 5% or 2% of the responseelicited by the natural agonist, C5a.

Additionally, preferred C5a receptor modulators do not inhibit or inducemicrosomal cytochrome P450 enzyme activities, such as CYP1A2 activity,CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity,CYP2E1 activity or CYP3A4 activity. Preferred C5a receptor modulatorsalso do not exhibit cytotoxicity in vitro or in vivo, are notclastogenic (e.g., as determined using a mouse erythrocyte precursorcell micronucleus assay, an Ames micronucleus assay, a spiralmicronucleus assay or the like) and do not induce sister chromatidexchange (e.g., in Chinese hamster ovary cells). Also preferred are C5areceptor modulators that inhibit the occurrence of C5a-induced oxidativeburst (OB) in inflammatory cells (e.g., neutrophil) as can beconveniently determined using an in vitro neutrophil OB assay.

For detection purposes, compounds provided herein may beisotopically-labeled or radiolabeled. Accordingly, compounds recited inFormula I (or any other formula specifically recited herein) may haveone or more atoms replaced by an atom of the same element having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be present incompounds provided herein include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl. In addition,substitution with heavy isotopes such as deuterium (i.e., ²H) can affordcertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.

Methods of Use

C5a modulators provided herein may be used as agonists or (preferably)antagonists of C5a receptors in a variety of contexts, both in vitro andin vivo. Within certain aspects, C5a antagonists may be used to inhibitthe binding of C5a receptor ligand (e.g., C5a) to C5a receptor in vitroor in vivo. In general, such methods comprise the step of contacting aC5a receptor with a sufficient amount of one or more substituted biarylamides as provided herein, in the presence of C5a receptor ligand inaqueous solution and under conditions otherwise suitable for binding ofthe ligand to C5a receptor. The C5a receptor may be present insuspension (e.g., in an isolated membrane or cell preparation), or in acultured or isolated cell. Within certain embodiments, the C5a receptoris expressed by a cell present in a patient, and the aqueous solution isa body fluid. In general, the amount of C5a receptor modulator contactedwith the receptor should yield a concentration in the aqueous solutionsufficient to inhibit C5a binding to C5a receptor in vitro as measured,for example, using a radioligand binding assay as described in Example19, a calcium mobilization assay as described in Example 21, or achemotaxis assay as described in Example 14. Preferably theconcentration is sufficient to inhibit chemotaxis of white blood cellsin an in vitro chemotaxis assay, so that the levels of chemotaxisobserved in a control assay (e.g., one to which a compound providedherein has not been added) are significantly higher (significance heremeasured as p≦0.05 using a conventional parametric statistical analysismethod such as a student's T-test) than the levels observed in an assayto which a compound as described herein has been added.

Also provided herein are methods for modulating, preferably inhibiting,the signal-transducing activity of a C5a receptor. Such modulation maybe achieved by contacting a C5a receptor (either in vitro or in vivo)with an effective amount of one or more C5a receptor modulators providedherein under conditions suitable for binding of the modulator(s) to thereceptor. The receptor may be present in solution or suspension, in acultured or isolated cell preparation or within a patient. Modulation ofsignal transducing activity may be assessed by detecting an effect oncalcium ion conductance (also referred to as calcium mobilization orflux) or by detecting an effect on C5a receptor-mediated cellularchemotaxis. In general, an effective amount of C5a modulator(s) is anamount sufficient to yield a concentration (in an aqueous solution thatis in contact with the receptor) that is sufficient to modulate C5areceptor signal transducing activity in vitro within a calciummobilization assay as described in Example 21 or C5a receptor-mediatedcellular chemotaxis within an assay as described in Example 14. C5areceptor modulator(s) provided herein are preferably administered to apatient (e.g., a human) orally or topically, and are present within atleast one body fluid of the animal while modulating C5a receptorsignal-transducing activity.

The present invention further provides methods for treating patientssuffering from conditions responsive to C5a receptor modulation. As usedherein, the term “treatment” encompasses both disease-modifyingtreatment and symptomatic treatment, either of which may be prophylactic(i.e., before the onset of symptoms, in order to prevent, delay orreduce the severity of symptoms) or therapeutic (i.e., after the onsetof symptoms, in order to reduce the severity and/or duration ofsymptoms). A condition is “responsive to C5a receptor modulation” ifmodulation of C5a receptor activity results reduction of inappropriateactivity of a C5a receptor, regardless of the amount of C5a receptorligand present locally and/or in alleviation of the condition or asymptom thereof. Patients may include primates (especially humans),domesticated companion animals (such as dogs, cats, horses) andlivestock (such as cattle, pigs, sheep), with dosages as describedherein.

Conditions that are responsive to C5a receptor modulation include thefollowing:

Autoimmune disorders—e.g., rheumatoid arthritis, systemic lupuserythematosus (and associated glomerulonephritis), psoriasis, Crohn'sdisease, vasculitis, irritable bowel syndrome, dermatomyositis, multiplesclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma,myasthenia gravis, autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome (and associated glomerulonephritis and pulmonaryhemorrhage), immunovasculitis, tissue graft rejection, and hyperacuterejection of transplanted organs.

Inflammatory disorders and related conditions—e.g., neutropenia, sepsis,septic shock, Alzheimer's disease, stroke, inflammation associated withsevere burns, lung injury, and ischemia-reperfusion injury,osteoarthritis, as well as acute (adult) respiratory distress syndrome(ARDS), systemic inflammatory response syndrome (SIRS), and multipleorgan dysfunction syndrome (MODS). Also included are pathologicsequellae associated with insulin-dependent diabetes mellitus (includingdiabetic retinopathy), lupus nephropathy, Heyman nephritis, membranousnephritis and other forms of glomerulonephritis, contact sensitivityresponses, and inflammation resulting from contact of blood withartificial surfaces that can cause complement activation, as occurs, forexample, during extracorporeal circulation of blood (e.g., duringhemodialysis or via a heart-lung machine, for example, in associationwith vascular surgery such as coronary artery bypass grafting or heartvalve replacement) such as extracorporeal post-dialysis syndrome, or inassociation with contact with other artificial vessel or containersurfaces (e.g., ventricular assist devices, artificial heart machines,transfusion tubing, blood storage bags, plasmapheresis,plateletpheresis, and the like).

Cardiovascular and Cerebrovascular Disorders—e.g., myocardialinfarction, coronary thrombosis, vascular occlusion, post-surgicalvascular reocclusion, atherosclerosis, traumatic central nervous systeminjury, and ischemic heart disease.

In a further aspect, C5a receptor modulators may be used to perfuse adonor organ prior to transplantation of the organ into a recipientpatient. Such perfusion is preferably carried out using a solution(e.g., pharmaceutical composition) comprising a concentration of themodulator that is sufficient to inhibit C5a receptor-mediated effects invitro and/or in vivo. Such perfusion preferably reduces the severity orfrequency of one or more of the inflammatory sequelae following organtransplantation when compared to that occurring in control (including,without restriction, historical control) transplant recipients who havereceived transplants of donor organs that have not been so perfused.

Treatment methods provided herein include in general administration to apatient an effective amount of one or more compounds of the invention.Suitable patients include those patients suffering from or susceptibleto (i.e., prophylactic treatment) a disorder or disease identifiedherein. Typical patients for treatment in accordance with the inventioninclude mammals, particularly primates, especially humans. Othersuitable patients include domesticated companion animals such as a dog,cat, horse, and the like, or a livestock animal such as cattle, pig,sheep and the like.

In general, treatment methods provided herein comprise administering toa patient an effective amount of a compound one or more compoundsprovided herein. The effective amount may be an amount sufficient tomodulate C5a receptor activity and/ or an amount sufficient to reduce oralleviate the symptoms presented by the patient. Preferably, the amountadministered is sufficient to yield a plasma concentration of thecompound (or its active metabolite, if a pro-drug) high enough todetectably inhibit white blood cell (e.g., neutrophil) chemotaxis invitro. Treatment regimens may vary depending on the compound used andthe particular condition to be treated; for treatment of most disorders,a frequency of administration of 4 times daily or less is preferred. Ingeneral, a dosage regimen of 2 times daily is more preferred, with oncea day dosing particularly preferred. It will be understood, however,that the specific dose level and treatment regimen for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination (i.e., other drugs being administered to thepatient) and the severity of the particular disease undergoing therapy,as well as the judgment of the prescribing medical practitioner. Ingeneral, the use of the minimum dose sufficient to provide effectivetherapy is preferred. Patients may generally be monitored fortherapeutic effectiveness using medical or veterinary criteria suitablefor the condition being treated or prevented.

As noted above, compounds and compositions provided herein are useful asinhibitors of C5a receptor-mediated chemotaxis (e.g., they may be usedas standards in assays of such chemotaxis). Accordingly, methods areprovided herein for inhibiting C5a receptor-mediated cellularchemotaxis, preferably leukocyte (e.g., neutrophil) chemotaxis. Suchmethods comprise contacting white blood cells (particularly primatewhite blood cells, especially human white blood cells) with one or morecompounds provided herein. Preferably the concentration is sufficient toinhibit chemotaxis of white blood cells in an in vitro chemotaxis assay,so that the levels of chemotaxis observed in a control assay aresignificantly higher, as described above, than the levels observed in anassay to which a compound as described herein has been added.

Within separate aspects, the present invention provides a variety ofnon-pharmaceutical in vitro and in vivo uses for the compounds providedherein. For example, such compounds may be labeled and used as probesfor the detection and localization of C5a receptor (in samples such ascell preparations or tissue sections, preparations or fractionsthereof). Compounds may also be used as positive controls in assays forC5a receptor activity, as standards for determining the ability of acandidate agent to bind to C5a receptor, or as radiotracers for positronemission tomography (PET) imaging or for single photon emissioncomputerized tomography (SPECT). Such methods can be used tocharacterize C5a receptors in living subjects. For example, a C5areceptor modulator may be labeled using any of a variety of well knowntechniques (e.g., radiolabeled with a radionuclide such as tritium, asdescribed herein), and incubated with a sample for a suitable incubationtime (e.g., determined by first assaying a time course of binding).Following incubation, unbound compound is removed (e.g., by washing),and bound compound detected using any method suitable for the labelemployed (e.g., autoradiography or scintillation counting forradiolabeled compounds; spectroscopic methods may be used to detectluminescent groups and fluorescent groups). As a control, a matchedsample containing labeled compound and a greater (e.g., 10-fold greater)amount of unlabeled compound may be processed in the same manner. Agreater amount of detectable label remaining in the test sample than inthe control indicates the presence of C5a receptor in the sample.Detection assays, including receptor autoradiography (receptor mapping)of C5a receptor in cultured cells or tissue samples may be performed asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York.

Modulators provided herein may also be used within a variety of wellknown cell separation methods. For example, modulators may be linked tothe interior surface of a tissue culture plate or other support, for useas affinity ligands for immobilizing and thereby isolating, C5areceptors (e.g., isolating receptor-expressing cells) in vitro. Withinone preferred embodiment, a modulator linked to a fluorescent marker,such as fluorescein, is contacted with the cells, which are thenanalyzed (or isolated) by fluorescence activated cell sorting (FACS).

Pharmaceutical Preparations

The present invention also provides pharmaceutical compositionscomprising one or more C5a receptor modulators provided herein, togetherwith at least one physiologically acceptable carrier or excipient.Pharmaceutical compositions may comprise, for example, one or more ofwater, buffers (e.g., neutral buffered saline or phosphate bufferedsaline), ethanol, mineral oil, vegetable oil, dimethylsulfoxide,carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol,proteins, adjuvants, polypeptides or amino acids such as glycine,antioxidants, chelating agents such as EDTA or glutathione and/orpreservatives. As noted above, other active ingredients may (but neednot) be included in the pharmaceutical compositions provided herein.

A carrier is a substance that may be associated with an active compoundprior to administration to a patient, often for the purpose ofcontrolling stability or bioavailability of the compound. Carriers foruse within such formulations are generally biocompatible, and may alsobe biodegradable. Carriers include, for example, monovalent ormultivalent molecules such as serum albumin (e.g., human or bovine), eggalbumin, peptides, polylysine and polysaccharides such as aminodextranand polyamidoamines. Carriers also include solid support materials suchas beads and microparticles comprising, for example, polylactatepolyglycolate, poly(lactide-co-glycolide), polyacrylate, latex, starch,cellulose or dextran. A carrier may bear the compounds in a variety ofways, including covalent bonding (either directly or via a linkergroup), noncovalent interaction or admixture.

Pharmaceutical compositions may be formulated for any appropriate mannerof administration, including, for example, topical, oral, nasal, rectalor parenteral administration. In certain embodiments, compositions in aform suitable for oral use are preferred. Such forms include, forexample, pills, tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsion, hard or soft capsules, orsyrups or elixirs. Within yet other embodiments, compositions providedherein may be formulated as a lyophilizate. The term parenteral as usedherein includes subcutaneous, intradermal, intravascular (e.g.,intravenous), intramuscular, spinal, intracranial, intrathecal andintraperitoneal injection, as well as any similar injection or infusiontechnique.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and may contain one or more agents sweetening agents,flavoring agents, coloring agent, and preserving agents in order toprovide appealing and palatable preparations. Tablets contain the activeingredient in admixture with physiologically acceptable excipients thatare suitable for the manufacture of tablets. Such excipients include,for example, inert diluents (e.g., calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate), granulating anddisintegrating agents (e.g., corn starch or alginic acid), bindingagents (e.g., starch, gelatin or acacia) and lubricating agents (e.g.,magnesium stearate, stearic acid or talc). The tablets may be uncoatedor they may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent(e.g., calcium carbonate, calcium phosphate or kaolin), or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium (e.g., peanut oil, liquid paraffin or olive oil).

Aqueous suspensions contain the active material(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents (e.g., sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia);and dispersing or wetting agents (e.g., naturally-occurring phosphatidessuch as lecithin, condensation products of an alkylene oxide with fattyacids such as polyoxyethylene stearate, condensation products ofethylene oxide with long chain aliphatic alcohols such asheptadecaethyleneoxycetanol, condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides such as polyethylene sorbitan monooleate). Aqueoussuspensions may also comprise one or more preservatives, for exampleethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents, and one or more sweetening agents, such assucrose or saccharin. Syrups and elixirs may be formulated withsweetening agents, such as glycerol, propylene glycol, sorbitol, orsucrose. Such formulations may also comprise one or more demulcents,preservatives, flavoring agents, and/or coloring agents.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil (e.g., arachis oil, olive oil, sesame oil, or coconutoil) or in a mineral oil such as liquid paraffin. The oily suspensionsmay contain a thickening agent such as beeswax, hard paraffin, or cetylalcohol. Sweetening agents, such as those set forth above, and/orflavoring agents may be added to provide palatable oral preparations.Such suspensions may be preserved by the addition of an anti-oxidantsuch as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil (e.g., olive oil orarachis oil), a mineral oil (e.g., liquid paraffin), or a mixturethereof. Suitable emulsifying agents include naturally-occurring gums(e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides(e.g., soy bean, lecithin, and esters or partial esters derived fromfatty acids and hexitol), anhydrides (e.g., sorbitan monoleate), andcondensation products of partial esters derived from fatty acids andhexitol with ethylene oxide (e.g., polyoxyethylene sorbitan monoleate).An emulsion may also comprise one or more sweetening and/or flavoringagents.

The pharmaceutical composition may be prepared as a sterile injectibleaqueous or oleaginous suspension in which the modulator, depending onthe vehicle and concentration used, is either suspended or dissolved inthe vehicle. Such a composition may be formulated according to the knownart using suitable dispersing, wetting agents and/or suspending agentssuch as those mentioned above. Among the acceptable vehicles andsolvents that may be employed are water, 1,3-butanediol, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils may be employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be usedin the preparation of injectible compositions, and adjuvants such aslocal anesthetics, preservatives and/or buffering agents can bedissolved in the vehicle.

C5a receptor modulators may also be administered in the form ofsuppositories (e.g., for rectal administration). Such compositions canbe prepared by mixing the drug with a suitable non-irritating excipientthat is solid at ordinary temperatures but liquid at the rectaltemperature and will therefore melt in the rectum to release the drug.Such materials are cocoa butter and polyethylene glycols.

Pharmaceutical compositions may be formulated as sustained releaseformulations (i.e., a formulation such as a capsule that effects a slowrelease of modulator following administration). Such formulations maygenerally be prepared using well known technology and administered by,for example, oral, rectal, or subcutaneous implantation, or byimplantation at the desired target site. Carriers for use within suchformulations are biocompatible, and may also be biodegradable;preferably the formulation provides a relatively constant level ofmodulator release. The amount of modulator contained within a sustainedrelease formulation depends upon, for example, the site of implantation,the rate and expected duration of release and the nature of thecondition to be treated or prevented.

In addition to or together with the above modes of administration, amodulator may be conveniently added to food or drinking water (e.g., foradministration to non-human animals including companion animals (such asdogs and cats) and livestock). Animal feed and drinking watercompositions may be formulated so that the animal takes in anappropriate quantity of the composition along with its diet. It may alsobe convenient to present the composition as a premix for addition tofeed or drinking water.

C5a receptor modulators provided herein are generally administered in anamount that achieves a concentration in a body fluid (e.g., blood,plasma, serum, CSF, synovial fluid, lymph, cellular interstitial fluid,tears or urine) that is sufficient to detectably inhibit the binding ofC5a to C5a receptor when assayed in vitro. A dose is considered to beeffective if it results in a discernible patient benefit as describedherein. Preferred systemic doses range from about 0.1 mg to about 140 mgper kilogram of body weight per day (about 0.5 mg to about 7 g perpatient per day), with oral doses generally being about 5-20 fold higherthan intravenous doses. The amount of active ingredient that may becombined with the carrier materials to produce a single dosage form willvary depending upon the host treated and the particular mode ofadministration. Dosage unit forms will generally contain between fromabout 1 mg to about 500 mg of an active ingredient.

Pharmaceutical compositions may be packaged for treating conditionsresponsive to C5a receptor modulation (e.g., rheumatoid arthritis,psoriasis, cardiovascular disease, reperfusion injury, bronchial asthma,Alzheimer's disease, stroke, myocardial infarction, atherosclerosis,ischemic heart disease or ischemia-reperfusion injury). Packagedpharmaceutical compositions may include a container holding a effectiveamount of at least one C5a receptor modulator as described herein andinstructions (e.g., labeling) indicating that the contained compositionis to be used for treating a condition responsive to C5a receptormodulation in the patient

Preparation of Compounds

Substituted biaryl amides provided herein may generally be preparedusing standard synthetic methods. In general, starting materials arecommercially available from suppliers such as Sigma-Aldrich Corp. (St.Louis, Mo.), or may be synthesized from commercially availableprecursors using established protocols. By way of example, a syntheticroute similar to that shown the following Schemes may be used, togetherwith synthetic methods known in the art of synthetic organic chemistry,or variations thereon as appreciated by those skilled in the art. Eachvariable in the following Schemes, such as an “R” or “Ar,” refers to anygroup consistent with the description of the compounds provided herein.An individual skilled in the art may find modifications of one orseveral of the synthetic steps described herein without divertingsignificantly from the overall synthetic scheme.

The preparation of ortho biarylamides described herein may be carriedout via a series of chemical transformations similar to those displayedgraphically in Scheme I.

As shown, the synthetic route begins with a benzoic acid of generalstructure A possessing a group X at the ortho position. This X group maybe iodine, bromine, chlorine, sulfonate ester orpolyfluoroalkylsulfonate ester. The benzoic acid may also be substitutedby up to four independently chosen substituents represented by thevariables R⁶. Examples of suitable substituents include, but are notlimited to, chlorine, fluorine, cyano, C₁-C₆ straight or branched chainalkyl, C₁-C₆ straight or branched chain alkoxy, trifluoromethyl,trifluoromethoxy, nitro, amino, mono- and di-alkylamino, sulfonamido,mono- and di-alkylsulfonamido, alkylthio (e.g., methylthio),alkylsulfoxide, alkylsulfone, acetyl, acetoxy, alkoxycarbonyl(—C═OO(alkyl)), or dialkylaminocarbonyl (—C═ON(alkyl)₂). Additionally,two adjacent R⁶ groups may be taken together with a chain of from 3 to 5methylene carbons to form an alkyl ring of from five to seven carbonsfused to the benzoic acid moiety. Additionally, two adjacent R⁶ groupsmay be taken together with an alkyloxy chain, for example —OCH₂O— or—OCH₂CH₂O—, to form an oxygen-containing moiety (in this examplemethylenedioxy or ethylenedioxy, respectively) fused to the benzoicacid.

The benzoic acid is then activated by conversion to an acid chloridewith thionyl chloride, oxalyl chloride or the like. Alternatively, itmay be activated by treatment with carbonyldiimidazole or a similaragent. The activated benzoic acid is then treated with an appropriatesecondary amine in the presence of base to provide a tertiary amide ofgeneral structure B.

Amide B is then converted to the biaryl structure C through the use ofaryl coupling reactions know in the chemical literature. Examples ofsuch reactions are the Stille reaction where an aryl trialkyltin reagentis coupled to an appropriate aryl in the presence of a catalyst such aspalladium or nickel; or a Suzuki reaction where an arylboronic acid iscoupled to an appropriate aryl in the presence of a nickel or palladiumcatalyst in the presence of base.

The group “Ar³” of General structure C may be a phenyl, naphthyl orother aromatic group, and may be optionally substituted with up to fiveadditional independently chosen substituents (e.g., hydrogen, halogen,cyano, C₁-C₆ straight or branched chain alkyl, C₁-C₆ straight orbranched chain alkoxy, trifluoromethyl, trifluoromethoxy, nitro, amino,mono- or di-alkyl amino, sulfonamido, mono or dialkylsulfonamido,alkylthio (e.g., methylthio), alkylsulfoxide, alkylsulfone, acetyl,acetoxy, hydroxycarbonyl (COOH), alkoxycarbonyl (—C═OO(alkyl)),aminocarbonyl (—CONH₂), monoalkylaminocarbonyl (—C═ONH(alkyl)),dialkylaminocarbonyl (—C═ON(alkyl)₂), methylenedioxy, or ethylenedioxy).

The Ar³ of General Structure C may also represent a heteroaryl groupsuch as 1- or 2-thienyl or 1- or 2- furanyl. Such a heteroaryl groupwhich may be additionally substituted by up to three independentlychosen substituents, such as halogen, cyano, C₁-C₆ straight or branchedchain alkyl, C₁-C₆ straight or branched chain alkoxy, trifluoromethyl,trifluoromethoxy, mono- or di-alkyl amino, sulfonamido, mono- anddi-alkylsulfonamido, alkylthio (e.g., methylthio), alkylsulfoxide,alkylsulfone, acetyl, acetoxy, hydroxycarbonyl, —COOH, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl.

Within Scheme 2 the variable X is a halogen, preferably chlorine orbromine.

As shown in Scheme 2, an appropriately substituted 1-napthoyl halide (D)is condensed with an appropriately substituted amine (E) in the presenceof a base, such as triethylamine or potassium carbonate or the like, toprovide compounds of Formula F, Compounds of general formulas D and Ecan be prepared by one of several methods described in the chemicalliterature.

Certain compounds provided herein contain one or more stereogeniccenters. In these situations, single enantiomers (i.e., optically activeforms) can be obtained by asymmetric synthesis, synthesis from opticallypure precursors or by resolution of the racemates. Resolution of theracemates can be accomplished, for example, by conventional methods suchas crystallization in the presence of a resolving agent, orchromatography, using, for example a chiral HPLC column.

The following Examples are offered by way of illustration and not by wayof limitation. Unless otherwise specified all reagents and solvent areof standard commercial grade and are used without further purification,or are readily prepared from such materials by routine methods. Thoseskilled in the art of organic synthesis will recognize that startingmaterials and reaction conditions may be varied to achieve the desiredend product.

EXAMPLES Abbreviations Used

The following abbreviations are used in Examples 1 to 5.

PyBroP Bromotris(pyrrolidino)phosphonium hexafluorophosphate

DMA dimethylacetamide NMM N-methylmorpholine t-BuOH tert-butanol CDI1,1′-carbonyl diimidazole DMF dimethylformamide SOCl₂ thionyl chloridePd(PPh₃)₄ tetrakis(triphenylphosphine) palladium (0) Na₂SO₄ sodiumsulfate CDCl₃ deuterochloroform THF tetrahydrofuran ¹H NMR protonnuclear magnetic resonance SiO₂ silica SPE solid phase extraction LCMSliquid chromatography/mass spectrometry HPLC high pressure liquidchromatography MHz megahertz Hz hertz MS mass spectrometry m/zmass/charge ratio (M + 1) mass + 1

Example 1 Preparation of 4′-Trifluoromethyl-biphenyl-2-carboxylic AcidBenzo[1,3]dioxol-5-ylmethyl-benzyl-amide

1,1′-carbonyldiimidazole (175 mg) is added to a solution of2-iodobenzoic acid (248 mg, 1 mmol) (1) in tetrahydrofuran (THF, 5 ml).The resulting mixture is stirred overnight at room temperature. Asolution of N-3,4-methylenedioxybenzyl-N-benzylamine (241 mg, 1equivalent) (2) in THF (2 mL) is added and the resulting solution isstirred for 1 hour, quenched with water, and extracted with diethylether. The organic extracts are dried (Na₂SO₄) and concentrated. Theresidual material is taken up in dimethoxyethane (10 mL) and a catalyticamount (20 mg) of tetrakis(triphenylphosphine)palladium(0) is added. Theresulting mixture is stirred under an argon atmosphere for 10 minutesand solid 4-trifluoromethyllphenylboronic acid (150 mg) is added in oneportion. A second phase of 1N aqueous Na₂SO₄ is added and the mixture iswarmed to 80° C. for 6 hours under an argon atmosphere. The solution iscooled, diluted with water and ethyl acetate and filtered through a padof celite. The organic phase is dried over sodium sulfate andconcentrated. Purification on silica eluting with 20% ethyl acetate inhexane provides the desired biphenylamide product (4). The proton NMRdisplays a doubled pattern commonly observed for amides which possesssome rotational restriction about the amide nitrogen at roomtemperature. The ratio of the rotomers is approximately equal. ¹H NMR(CDCl₃) 3.50 and 3.62 (two doublets, J=X Hz, 1H), 3.72 and 3.83 (twodoublets, J=X Hz, 1H), 4.10 and 4.18 (two doublets, J=X Hz, 1H), 5.09and 5.16 (two doublets, J=x Hz, 1H), 5.95 (d, J=X Hz, 2H, OCH₂O), 6.30(m, 1.5 H), 6.46 (d, J=1 Hz, 0.5 Hz), 6.60 and 6.66 (two doublets, J=XHz, 1H), 6.80 (bd, J=X Hz, 1H), 6.86 (m, 1H), 7.16-7.62 (m, 11 H).

Example 2 Preparation of 3-Methyl-biphenyl-2-carboxylic AcidBenzyl-indan-2-yl-amide

Step A.

Thionyl chloride (1 ml) is added to a suspension of 2-Iodo-6-methylbenzoic acid (665 mg, 2.5 mmol) (5) in 10 ml of toluene. The mixture isstirred at 80° C. for 2 hours; the solvent and the remaining thionylchloride are then evaporated. The residue is dissolved in 5 ml ofanhydrous tetrahydrofuran and added to a solution ofbenzyl-indan-2-yl-amine (557 mg, 2.5 mmol) in 10 ml of tetrahydrofurancontaining 506 mg of triethylamine at 0° C. The resulting mixture isstirred at room temperature overnight, diluted with 20 ml of ethylacetate, washed with water and brine, and dried over sodium sulfate.Concentration and purification by silica gel chromatography affordscompound 6. MS (+VE) m/z 467 (M+1).Step B.

Aqueous sodium carbonate solution (1.0 ml of 2.0N) and a solution ofphenyl boronic acid (40 mg, 0.325 mmol) in 0.3 ml ethanol is added to asolution of compound 6 (117 mg, 0,25 mmol) and Pd(PPh₃)₄ (13 mg, 0.015mmol) in 2 ml of toluene under N₂. The resulting mixture is stirred at80° C. overnight. The mixture is cooled to room temperature, dilutedwith 20 ml of ethyl acetate, washed with water and brine, dried, andconcentrated. The crude product is purified by silica gel chromatographyto give 97 mg of product 7. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.60 (4H, m),6.90-7.30 (11H, m), 6.75 (2H, m), 4.75 (1H, d, J=15.5 Hz), 4.39 (1H, m),4.30 (1H, d, J=15.6 Hz), 2.80 (2H, m), 2.44 (3H, s), 2.28 (2H, m). MS(+VE) m/z 418 (M⁺).

Example 3 Preparation ofN-benzyl-N-(2-methyl-benzyl)-2-pyrrol-1-yl-benzamide

2-Pyrrol-1-yl-benzoic acid (3.7 mg; 1 equiv.) (8) is dissolved to 0.2 Min DMA containing triethylamine (5% v/v). A solution of benzylamine (0.2M in toluene containing NMM (5% v/v); 0.10 ml; 1 equiv.) is addedfollowed by a solution of PyBroP (0.2 M in THF; 0.12 ml; 1.2 equiv.).The resulting solution, containing intermediate (9), is shaken at roomtemperature for 3 hours. A solution of 2-methylbenzyl bromide (0.2 M intoluene; 0.15 ml; 1.5 equiv.) is then added followed by potassiumtert-butoxide (0.5 M in THF/t-BuOH (1:1, v/v); 0.16 ml; 4 equiv.). Thesolution is heated to 50° C. for 3 hours, and then cooled to roomtemperature and treated with saturated ammonium chloride (0.35 ml). Thereaction is extracted with isopropyl ether (0.5 ml), and the upperorganic layer is deposited on a silica gel SPE cartridge (0.5 g SiO₂).The cartridge is eluted with 25% ethyl acetate in hexanes (4 ml), andthe eluted solution is concentrated under reduced pressure, to providethe desired product (10). LCMS: target mass 381.20 (M+H)⁺; observed mass381.15 (M+H)⁺; 92% spectrum purity.

Example 4 Preparation ofN-indan-2-yl-N-(3-methyl-benzyl)-2-pyrrol-1-yl-benzamide

2-Pyrrol-1-yl-benzoic acid (3.7 mg; 1 equiv.) (8) is dissolved to 0.2 Min DMA containing triethylamine (5% v/v). A solution of indan-2-ylamine(0.2 M in toluene containing NMM (5% v/v); 0.10 ml; 1 equiv.) is addedfollowed by a solution of PyBroP (0.2 M in THF; 0.12 ml; 1.2 equiv.).The resulting solution is shaken at room temperature for 3 hours. Thesolution is then treated with potassium tert-butoxide (0.5 M inTHF/t-BuOH (1:1, v/v); 0.15 ml; 3.75 equiv.) and 3-methylbenzyl bromide(0.2 M in Toluene; 0.125 ml; 1.25 equiv.). The reaction is shaken atroom temperature for 20 minutes, and then retreated with 3-methylbenzylbromide (0.2 M in Toluene; 0.05 ml; 0.5 equiv.) and potassiumtert-butoxide (0.5 M in THF/t-BuOH (1:1, v/v); 0.025 ml; 1.25 equiv.).The reaction is shaken again at room temperature for 20 minutes andretreated with 3-methylbenzyl bromide (0.2 M in toluene; 0.05 ml; 0.5equiv.) and potassium tert-butoxide (0.5 M in THF/t-BuOH (1:1, v/v);0.025 ml; 1.25 equiv.). The reaction is then heated to 50° C. for 2hours, then cooled to room temperature, and treated with saturatedammonium chloride (0.5 ml). The reaction is extracted with isopropylether (0.5 ml), and the upper organic layer is deposited on a silica gelSPE cartridge (0.5 g SiO₂). The cartridge is eluted with 25% ethylacetate in hexanes (4 ml), and the eluted solution is concentrated underreduced pressure, to yield the title compound (11). LCMS: target mass407.21 (M+H)⁺; observed mass 407.25 (M+H)⁺; 92% spectrum purity.

Example 5 Preparation of 2-methoxy-naphthalene-1-carboxylic AcidBenzyl-indan-2-yl-amide

2-Methoxynapthoic acid (202 mg, 1 mmol) is dissolved in thionyl chloride(1 ml). The resulting solution is refluxed for 2 hours. The thionylchloride is evaporated on a rotary evaporator, the residue taken up intoluene (5 ml), and reconcentrated. The resulting 2-methoxynapthoylchloride (12) is dissolved in dry tetrahydrofuran (5 ml) containingtriethylamine (278 microliters, 2 mmol) and dimethylaminopyridine (DMAP,20 mg). A solution of N-benzyl-N-indan-2-ylamine (179 mg, 0.8 mmol) (13)is added to the 2-methoxynapthoyl chloride solution and the resultingsolution is stirred overnight. A solution of sodium bicarbonate (3N, 5ml) is added and the mixture extracted with ethyl acetate (3×20 ml). Theorganic extracts are then washed with water and brine, dried over sodiumsulfate, and concentrated. The crude product is purified by silica gelchromatography to provide the desired compound (14) as an oil. LC-MS 408(M+1), ¹H NMR (CDCl₃) 7.87 (d, J=2 Hz, 1H), 7.72-7.82 (m, 2H), 7.52 (t,J=2 Hz, 1H), 7.45 (d, 2Hz, 1H), 6.96-7.40 (m, 10H), 5.22 (d, J=4 Hz,1H), 4.65 (d, J=4 Hz, 1H), 4.6 (t, J=2 Hz, 1H), 4.04 (s, 3H, OMe),2.95-3.08 (m, 2H), 2.86 (dd, J=4, 2 Hz, 1H), 2.68 (J=4, 2 Hz, 1H) ppm. Aminor amide rotational isomer with the methoxy group at 3.87 ppm is alsoobservable.

Example 6 Preparation of2-(5-methyl-thiophen-2-yl)-naphthalene-1-carboxylic AcidIndan-2-yl-(2-fluoro-benzyl)-amide

Step A. Synthesis of 2-methoxy-naphthalene-1-carboxylic AcidIndan-2-yl-(2-fluoro-benzyl)-amide

The above compound (16) is prepared in by the method described inExample 5.Step B. Synthesis of 2-Hydroxy-naphthalene-1-carboxylic AcidIndan-2-yl-(2-fluoro-benzyl)-amide

Boron tribromide (1N in dichloromethane, 1 mL) is added at −78° C. undernitrogen to a solution of 2-methoxy-naphthalene-1-carboxylic acidindan-2-yl-(2-fluoro-benzyl)-amide (16) (421 mg; 1 mmol) in anhydrousdichloromethane (5 mL). The mixture is then stirred at room temperatureovernight. After cooling to 0° C., water is added to quench thereaction. The organic phase is separated, dried over anhydrous sodiumsulfate, and concentrated. The residue is purified by columnchromatography to provide the title compound (17) as a white solid (365mg, 90%). LC-MS [MH+] 412; ¹H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H); 7.73(t, J=7.2 Hz, 2H), 7.53-7.48 (m, 1H), 7.42-7.32 (, m, 2H), 7.20 (m, 2H),7.09-6.98 (m, 5H), 6.81 (d, J=9.0 Hz, 1H), 4.74 (m, 2H), 3.16 (m, 1H),2.98-2.20 (m, 2H), 2.36 (s, 2H).Step C. Synthesis of Trifluoro-methanesulfonic Acid1-[Indan-2-yl-(2-fluoro-benzyl)-carbamoyl]-napthalen-2-yl Ester

Trifluoromethanesulfonic acid anhydrous (0.27 mL, 1.6 mmol) is addeddropwise in 10 minutes to a solution of2-hydroxy-naphthalene-1-carboxylic acidindan-2-yl-(2-fluoro-benzyl)-amide (17) (323 mg, 0.8 mmol) in anhydrouspyridine (5 mL) at 0° C. under nitrogen. The mixture is stirred at roomtemperature overnight and concentrated under reduced pressure. Theresidue (18) is dried in vacuo and used for the next step withoutfurther purification.

Step D. Synthesis of 2-(5-methyl-thiophen-2-yl)-naphthalene-1-carboxylicAcid Indan-2-yl-(2-fluoro-benzyl)-amide

A mixture of the trifluoromethanesulfonic acid1-[indan-2-yl-(2-fluoro-benzyl)-carbamoyl]-naphthalen-2-yl ester (18),5-methyl-2-thiophene boronic acid (19) (142 mg, 1 mmol) and Pd(PPh)₄ (50 mg) in 2 mL of 1 N sodium carbonate and toluene (v/v=1/1) in sealtube under nitrogen was heated at 90° C. for 16 hours. After cooling toroom temperature, the organic phase is separated and the aqueous phaseextracted with ethyl acetate. The combined organic phases are washedwith 1N HCl, saturated sodium bicarbonate and brine, dried overanhydrous sodium sulfate, and concentrated. The residue is purified bysilica gel column chromatography to yield the desired product (20) (72mg, 19% in two steps). LC-MS [MH+] 492.

Example 7 Synthesis of 1,5-Dimethyl-1H-indole-4-carboxylic AcidIndan-2-yl-(4-methyl-benzyl)-amide

Step A. Synthesis of 4-bromo-5-methylindole

Fuming nitric acid (>90% yellow fuming HNO₃) is slowly added to asolution of 2-bromo-m-xylene (20 g, 150 mmol) in acetic acid (100 ml)cooled in an ice bath (above freezing point). The resulting mixture isallowed to warm to room temperature, stirred for 1 hour, and heated at80° C. for 2 hours or until the reaction is shown to be complete byGC/MS analysis following micro-scale base work-up. The reaction mixtureis cooled to room temperature and poured into ice/water with stirring.The resulting yellow precipitates are collected by suction filtrationand air dried to obtain 2,6-dimethyl-3-nitrobromobenzene.

Bredereck's reagent (tert-butoxybis(dimethylamino)methane—16 g, 91 mmol)is added at room temperature to a solution of2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120ml). The reaction mixture is heated at 120-125° C. under N₂ for 5 hoursor until starting material is mostly consumed according to TLC. Thereaction mixture is allowed to cool to room temperature, poured intowater (300 ml), and extracted with dichloromethane (100 ml×3). Thecombined extracts are dried over anhydrous sodium sulfate, filtered, andconcentrated to obtain a mixture of enamines as a dark brown oil. Thismaterial is carried on to the next step without purification. The crudemixture is dissolved in acetic acid/water (250 ml of 4:1), cooled to 0°C. and treated with zinc dust (57 g, 870 mmol) added slowly in portions.After complete addition, the reaction mixture is heated at 110° C. for 4h. Zinc is removed by filtration through a celite pad and the filtrateis extracted with dichloromethane (100 ml×3). The combined extracts aredried over anhydrous sodium sulfate, concentrated and purified by flashchromatography on silica get (EtOAc/Hexane 1:20) to obtain4-bromo-5-methylindole (5.3 g) (21) as a light purple oil.

Step B. Preparation of 4-bromo-1,5-dimethyl-1H-indole

A solution of 4-bromo-5-methylindole (3.55 g, 16.9 mmol) (21) in 10 mlof anhydrous DMF is added to a suspension of sodium hydride (1.01 g, 60%in mineral oil, 25.3 mmol, 1.5 eq.) in 10 ml of DMF under nitrogen at 0°C. The resulting mixture is stirred at 0° C. for 30 minutes, and thenwarmed to room temperature. After stirring at room temperature for anadditional 2 hours, the reaction mixture is cooled to 0° C. Iodomethane(2.40 g, 18.6 mmol, 1.1 eq.) is added dropwise, the mixture is stirredat 0° C. for 2 hours, and then is warmed to 50° C. and stirred for anadditional 2 hours. The reaction mixture is poured into 100 ml ofice-water, extracted with ethyl acetate (30 ml×3), washed with water andbrine dried over anhydrous sodium sulfate. The solvent is evaporated andthe product (22) is taken to dryness under high vacuum to give 3.75 g ofpure compound. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (1H, d, J=8.4 Hz), 7.08(1H, d, J=8.4 Hz), 7.05 (1H, 4, J=3.2 Hz), 650 (1H, dd, J=0.4, 2.8 Hz),3.77 (3H, 3), 2.51 (3H, s); MS (+VE) m/z 224 (M⁺).

Step C. Preparation of 1,5-Dimethyl-1H-indole-4-carboxylic Acid

N-BuLi (1.6 M in hexane, 3.45 ml, 5.5 mmol, 1.1 eq.) is added undernitrogen to a solution of 4-bromo-1,5-dimethylindole (1.12 g, 5 mmol)(22) in 20 ml anhydrous tetrahydrofuran cooled to −78° C. The resultingsolution is stirred at −78° C. for 30 minutes and then quenched byintroducing anhydrous carbon dioxide gas. The reaction mixture is raisedto room temperature slowly, 20 ml of water is added into the flask andthe tetrahydrofuran is evaporated at reduced pressure. The resultingaqueous solution is adjusted to pH 5-6 with 1.0 N hydrochloric acid. Theproduct is extracted with ethyl acetate (25 ml×3), washed with water andbrine, dried over anhydrous sodium sulfate, concentrated, and taken todryness under high vacuum to give 927 mg of1,5-Dimethyl-1H-indole-4-carboxylic acid (23). ¹H NMR (400 MHz, CDCl₃) δ7.40 (1H, d, J=8.4 Hz), 7.15 (1H, d, J=3.2 Hz), 7.12 (1H, d, J=8.0Hz),7.02 (1H, dd, J=0.8, 3.2 Hz), 3.81 (3H, s), 2.75 3H, s). MS (+VE) m/z190 (M⁺+1).

Step D. Preparation of 1,5-Dimethyl-1H-indole-4-carboxylic AcidIndan-2-yl-(4-methyl-benzyl)-amide

EDCI (2 equivalents), HOBT (1 equivalent), and 2.0 equivalents oftriethylamine are added to a solution of1,5-Dimethyl-1H-indole-4-carboxylic acid (23) (189 mg, 1.0 mmol) and(4-tolyl)-indan-2-ylamine (237 mg, 1.0 mmol, 1.0 eq.) (24) in 10 ml ofanhydrous 1,2-dichloroethane. The resulting solution is stirred at roomtemperature for 5 hours and heated at reflux overnight. The reactionmixture is diluted with dichloromethane (20 ml), extracted withsaturated sodium bicarbonate solution (10 ml×2), water (10 ml×2), andbrine (10 ml). The organic layer is dried over anhydrous sodium sulfate,filtered and evaporated at reduced pressure, and purified byreverse-phase preparative HPLC to obtain1,5-dimethyl-1H-indole-4-carboxylic acidindan-2-yl-(4-methyl-benzyl)-amide (25).

Example 7A Preparation of 1,5-Dimethyl-1H-indole-4-carboxylic Acid(4-Dimethylamino-benzyl)-(4-isopropyl-phenyl)-amide

This compound (26) may be prepared by the procedure described in thepreceding example using 4-carboxy-1,5-dimethylindole and(4-isopropylphenyl)-(4′-dimethylamino)benzylamine as starting materials.

Example 8 Preparation of 5-isopropyl-1-methyl-1H-indazole-4-carboxylicAcid Indan-2-yl-(4-methyl-benzyl)-amide

Step A. Preparation of 4-Bromo-5-isopropyl-1-methylindole (28)

A solution of 4-bromo-5-isopropylindazole (27) (488 mg, 2.04 mmol) in 5ml of anhydrous DMF is added to a suspension of sodium hydride (122 mg,60% in mineral oil, 3.06 mmol, 1.5 eq.) in 5 ml of DMF under nitrogen at0° C. The resulting mixture is stirred at 0° C. for 30 minutes, thenwarmed to room temperature. After stirring at room temperature for anadditional 2 hours, the reaction mixture is cooled to 0° C., andiodomethane (318 mg, 2.24 mmol, 1.1 eq.) is added dropwise, the mixtureis stirred at 0° C. for 2 hours, then warmed to room temperature, andstirred overnight. The reaction mixture is poured into 30 ml ofice-water, extracted with ethyl acetate (30 ml×3), washed with water andbrine, and dried over anhydrous sodium sulfate. The solvent isevaporated and the product is purified via flash chromatography to give340 mg of 4-bromo-5-isopropyl-1-methylindazole ¹H NMR (400 MHz, CDCl₃)7.95 (1H, s), 7.31 (2H, S), 4.05 (3H, S), 3.55 (1H, m), 1.27 (6H, d,J=6.8Hz). MS (+VE) m/z 253(M⁺). 165 mg of4-bromo-5-isopropyl-2-methylindazole (28). ¹H NMR (400 MHz, CDCl₃) δ7.82 (1H, s), 7.59 (1H, d, J=9.2 Hz), 7.21 (1H, d, J=8.8 Hz), 4.16 (3H,s), 3.50 (1H, m), 1.21 (6H, d, J=6.8 Hz). MS (+VE) m/z 253(M⁺).

Step B. Preparation of 5-Isopropyl-1-methyl-1H-indazole-4-carboxylicAcid

BuLi (1.6 M in hexane, 925 ul, 1.47 mmol, 1.1 eq.) is added undernitrogen to a solution of 4-bromo-5-isopropyl-1-methylindazole (340 mg,1.34 mmol) (28) in 10 ml anhydrous tetrahydrofuran cooled to −78° C. Theresulting solution is stirred at −78° C. for 30 minutes. The anion isquenched by introducing anhydrous carbon dioxide gas, the flask israised to room temperature slowly. Water (20 ml) is added to the flask,the tetrahydrofuran is evaporated, and the aqueous solution is adjustedto pH 5-6 with 1.0 N hydrochloric acid. The product is extracted withethyl acetate (15 ml×3), washed with water and brine, dried overanhydrous sodium sulfate, concentrated, and taken to dryness under highvacuum to give 270 mg of pure product (29). MS (+VE) m/z 219 (M⁺+1).

Step C. Preparation of -Isopropyl-1-methyl-1H-indazole-4-carbonylChloride

2.0 N oxalychloride-dichloromethane solution (3.1 ml, 6.2 mmol, 5 eq.)is added to a solution of 5-isopropyl-1-methyl-1H-indazole carboxylicacid (270 mg, 1.24 mmol) in a mixture of 5 ml of cyclohexane and 5 ml ofanhydrous THF containing one drop of DMF. The resulting solution isstirred at room temperature overnight. The solvents are evaporated; 10ml of toluene is added, and the mixture is evaporated to dryness againto give 5-isopropyl-1-methyl-1H-indazole-4-carbonyl chloride (30) asbrown foam.

Step D. Preparation of 5-Isopropyl-1-methyl-1H-indazole-4-carboxylicAcid Indan-2-yl-(4-methyl-benzyl)-amide

5-Isopropyl-1-methyl-1H-indazole-4-carbonyl chloride (0.618 mmol, 1.0eq) (30) in 5 ml of THF is added to a solution of(4-tolyl)-indan-2-yl-amine (147 mg, 0.618 mmol) (31) in 5 ml oftetrahydrofuran containing 250 mg of triethylamine at 0° C. Theresulting mixture is stirred at room temperature overnight, diluted with20 ml of ethyl acetate, washed with water and brine, and dried oversodium sulfate. Concentration and purification by silica gelchromatography affords 168 mg of5-isopropyl-1-methyl-1H-indazole-4-carboxylic acidindan-2-yl-(4-methyl-benzyl)-amide (32). ¹H NMR (400 MHz, CDCl₃) 7.89(1H, s), 7.42˜6.92 (10H, m), 4.95 (1H, d, J=15.2 Hz), 4.66 (1H, d,J=15.2 Hz), 4.551 (1H, m), 4.05 (3H, s), 3.26˜2.73 (5H, m), 2.36 (3H,s), 1.34 (6H, dd, J=1.6, 6.8Hz). MS (+VE) m/z 438 (M⁺+1).

Example 8A Preparation of 5-Isopropyl-1-methyl-1H-indazole-4-carboxylicAcid (4-di-methylamino-benzyl)-(4-isopropyl-phenyl)-amide

5-Isopropyl-1-methyl-1H-indazole-4-carbonyl chloride (0.618 mmol, 1.0eq.) in 5 ml of THF is added to a solution of(4-isopropylphenyl)-(4′-dimethylamino)benzylamine (165 mg, 0.618 mmol)in 5 ml of tetrahydrofuran containing 250 mg of triethylamine at 0° C.The resulting mixture is stirred at room temperature overnight, dilutedwith 20 ml of ethyl acetate, washed with water and brine, and dried oversodium sulfate. Concentration and purification by silica gelchromatography affords 157 mg of5-isopropyl-1-methyl-1H-indazole-4-carboxylic acid(4-dimethylamino-benzyl)-(4-isopropyl-phenyl)-amide (32A). ¹H NMR (400MHz, CDCl₃) 7.83 (1H, s), 7.27˜7.08 (4H, m), 6.79˜6.67 (6H, m), 5.38(1H, D, J=14 Hz), 4.78 (1H, d, J=14 Hz), 3.95 (3H, s), 3.11 (1H, m),2.95 (6H, s), 2.64 (1H, m)1.24 (6H, d, J=6.4 Hz), 1.02 (6H, d, J=6.8Hz).MS (+VE) m/z 469 (M⁺+1).

Example 9 Synthesis of5-Isopropyl-1-methyl-1H-benzoimidazole-4-carboxylic Acid(4-dimethylamino-benzyl)-(4-isopropyl-phenyl)-amide

Acylchloride 0.618 mmol, 1.0 eq.) in 5 ml of THF (30) is added to thesolution of (4-isopropylphenyl)-(4′-dimethylamino)benzylamine (33) (165mg, 0.618 mmol) in 5 ml of tetrahydrofuran containing 250 mg oftriethylamine at 0° C. The resulting mixture is stirred at roomtemperature overnight, diluted with 20 ml of ethyl acetate, washed withwater and brine, and dried over sodium sulfate. Concentration andpurification by silica gel chromatography affords 157 mg of amidecompound (34) (54% of yield). ¹H NMR (400 MHz, CDCl₃) 7.83 (1H, s),7.27˜7.08 (4H, m), 6.79˜6.67 (6H, m), 5.38 (1H, D, J=14 Hz), 4.78 (1H,d, J=14 Hz), 3.95 (3H, s), 3.11 (1H, m), 2.95 (6H, s), 2.64 (1H, m)1.24(6H, d, J=6.4 Hz), 1.02 (6H, d, J=6.8Hz). MS (+VE) m/z 469 (M⁺+1).

Example 10 Additional Compounds

Additional substituted biarylamides are shown in Tables I-III. Thecompounds shown in Table I are prepared via the method provided inScheme 1 and further illustrated in Examples 1 and 2. The compoundsshown in Table II are prepared via the methods provided in Examples 3and 4. The compounds in Table III are prepared via the method providedin Scheme 2 and further illustrated in Examples 5 and 6. Compounds thathave an asterisk in the column labeled “Ca²⁺ Mob.”, were tested in thestandard assay of C5a receptor mediated calcium mobilization given inExample 18 and found to exhibit a Ki of less than 1 μM.

All compounds in Table II were tested in the radioligand binding assay(Example 17) and found to inhibit C5a binding to the human C5a receptor95% or more.

The LC/MS data presented in Tables I, II, and III were obtained usingthe following instrumentation and methods. MS spectroscopy data isElectrospray MS, obtained in positive ion mode, with a 15V Cone voltage,using a WATERS ZMD 2000 Mass Spec Detector, equipped with a WATERS 600pump, WATERS 2487 Dual Wavelength Detector, GILSON 215 Autosampler, anda GILSON 841 Microinjector. MassLynx version 3.4 software was used fordata collection and analysis.

Sample, 2-20 microliters, was injected onto a 33×4.6 mm YMC ProPack C18;5 micron column, and eluted using a 2-phase linear gradient at a 4mL/minute flow rate. Sample was detected at 220 and 254 nm. The elutionconditions were as follows: Mobile Phase A- 95/5/0.1 Water/Methanol/TFA,Mobile Phase B- 5/95/0.1 Water/Methanol/TFA.

Gradient time(min) % B 0 10 2.0 100 3.5 100 3.51 10

The total run time for the gradient was 4.0 minutes

TABLE I CMP Ca2+ # STRUCTURE Mob. IUPAC Name 34

* N,N-dibenzyl-4′-fluoro-1,1′- biphenyl-2-carboxamide 35

* 3′-(acetylamino)-N,N-dibenzyl- 1,1′-biphenyl-2-carboxamide 36

* N,N-dibenzyl-4′- (trifluoromethoxy)-1,1′-biphenyl- 2-carboxamide 37

* N,N-dibenzyl-2′-(methylthio)- 1,1′-biphenyl-2-carboxamide 38

* N,N-dibenzyl-4′-(ethylthio)-1,1′- biphenyl-2-carboxamide 39

* N,N-dibenzyl-3′-fluoro-1,1′- biphenyl-2-carboxamide 40

* N,N-dibenzyl-3′,4′-dimethyl-1,1′- biphenyl-2-carboxamide 41

* N,N-dibenzyl-2-thien-3- ylbenzamide 42

* N,N-dibenzyl-4′- (trifluoromethyl)-1,1′-biphenyl-2- carboxamide 43

* N,N-dibenzyl-2′-methoxy-1,1′- biphenyl-2-carboxamide 44

* N,N-dibenzyl-4′-methoxy-1,1′- biphenyl-2-carboxamide 45

* N,N-dibenzyl-2′,4′-dimethoxy- 1,1′-biphenyl-2-carboxamide 46

* N,N-dibenzyl-3′,4′-dimethoxy- 1,1′-biphenyl-2-carboxamide 47

* N,N-dibenzyl-1,1′-biphenyl-2- carboxamide 48

* N,N-dibenzyl-2′-chloro-1,1′- biphenyl-2-carboxamide 49

* N,N-dibenzyl-3′-chloro-1,1′- biphenyl-2-carboxamide 50

* N,N-dibenzyl-4′-chloro-1,1′- biphenyl-2-carboxamide 51

* N,N-dibenzyl-2′,3′-dichloro-1,1′- biphenyl-2-carboxamide 52

* N,N-dibenzyl-2′,4′-dichloro-1,1′- biphenyl-2-carboxamide 53

* N,N-dibenzyl-2′-methyl-1,1′- biphenyl-2-carboxamide 54

* N,N-dibenzyl-3′-methyl-1,1′- biphenyl-2-carboxamide 55

* N,N-dibenzyl-4′-methyl-1,1′- biphenyl-2-carboxamide 56

* N,N-dibenzyl-3′,5′-dichloro-1,1′- biphenyl-2-carboxamide 57

N-benzyl-N-[2-(4- methoxyphenyl)-1-methylethyl]-4′-methyl-1,1′-biphenyl-2- carboxamide 58

* N-benzyl-N-(indan-2-yl)-4′- methyl-1,1′-biphenyl-2- carboxamide 59

* N-benzyl-N-(indan-2-yl)-2-(4- methylthien-2-yl)benzamide 60

* N-benzyl-N-(indan-2-yl)-1,1′- biphenyl-2-carboxamide 61

* N-benzyl-N-(indan-1-yl)-2′- fluoro-1,1′-biphenyl-2- carboxamide 62

* N-benzyl-N-(indan-2-yl)-3′- methoxy-1,1′-biphenyl-2- carboxamide 63

* N-benzyl-N-(indan-2-yl)-2-thien- 2-ylbenzamide 64

* N-(1,3-benzodioxol-5-ylmethyl)- N-(indan-2-yl)-3′-methoxy-1,1′-biphenyl-2-carboxamide 65

* N-(1,3-benzodioxol-5-ylmethyl)- N-(indan-2-yl)-9H-fluorene-4-carboxamide 66

* N-benzyl-N-(indan-2-yl)-4- methoxy-1,1′-biphenyl-2- carboxamide 67

* N-benzyl-N-(indan-2-yl)-3- methoxy-1,1′-biphenyl-2- carboxamide 68

* N-benzyl-N-(indan-2-yl)-4- hydroxy-1,1′-biphenyl-2- carboxamide 69

* N-benzyl-N-(indan-2-yI)-3- hydroxy-1,1′-biphenyl-2- carboxamide 70

* N-benzyl-N-(indan-2-yl)-5- methoxy-2-(5-methylthien-2- yl)benzamide 71

* N-benzyl-N-(5-methoxy-indan-2- yl)-1,1′-biphenyl-2-carboxamide 72

* N-benzyl-N-(5-methyl-indan-2- yl)-1,1′-biphenyl-2-carboxamide 73

* N-(indan-2-yl)-N-(2- methylbenzyl)-1,1′-biphenyl-2- carboxamide 74

* N-(indan-2-yl)-N-(3- methylbenzyl)-1,1′-biphenyl-2- carboxamide 75

* N-(indan-2-yl)-N-(4- methylbenzyl)-1,1′-biphenyl-2- carboxamide 76

* N-(indan-2-yl)-N-(4- fluorobenzyl)-1,1′-biphenyl-2- carboxamide 77

* N-(indan-2-yl)-N-(3- fluorobenzyl)-1,1′-biphenyl-2- carboxamide 78

* N-(indan-2-yl)-N-(2- fluorobenzyl)-1,1′-biphenyl-2- carboxamide 79

* N-(1,3-benzodioxol-5-ylmethyl)- N-(indan-2-yl)-1,1′-biphenyl-2-carboxamide 80

* N-(3,4-difluorobenzyl)-N-(indan- 2-yl)-1,1′-biphenyl-2- carboxamide 81

* N-(indan-2-yl)-N-(2- methoxybenzyl)-2-thien-3- ylbenzamide 82

* N-(indan-2-yl)-2′-fluoro-N-(2- methoxybenzyl)-1,1′-biphenyl-2-carboxamide 83

* N-(indan-2-yl)-N-(4- methoxybenzyl)-2-thien-3- ylbenzamide 84

* N-(indan-2-yl)-N-(3,5- dimethoxybenzyl)-2-thien-3- ylbenzamide 85

* N-(indan-2-yl)-2-thien-3-yl-N-(3- thien-3-ylbenzyl)benzamide 86

* N-(indan-2-yl)-N-(2- naphthylmethyl)-2-thien-3- ylbenzamide 87

* N,N-dibenzyl-2′-fluoro-1,1′- biphenyl-2-carboxamide 88

* N-(indan-2-yl)-4′-methyl-N-(4- methylbenzyl)-1,1′-biphenyl-2-carboxamide 89

* N-(indan-2-yl)-3′-methoxy-N-(4- methylbenzyl)-1,1′-biphenyl-2-carboxamide 90

* N-(indan-2-yl)-2′-fluoro-N-(4- methylbenzyl)-1,1′-biphenyl-2-carboxamide 91

* N-(indan-2-yl)-N-(4- fluorobenzyl)-4′-methyl-1,1′-biphenyl-2-carboxamide 92

* N-(indan-2-yl)-N-(4- fluorobenzyl)-3′-methoxy-1,1′-biphenyl-2-carboxamide 93

* N-(indan-2-yl)-2′-fluoro-N-(4- fluorobenzyl)-1,1′-biphenyl-2-carboxamide 94

* N-(indan-2-yl)-N-(2- fluorobenzyl)-4′-methyl-1,1′-biphenyl-2-carboxamide 95

* N-(indan-2-yl)-N-(3- fluorobenzyl)-4′-methyl-1,1′-biphenyl-2-carboxamide 96

* N-(indan-2-yl)-2′-fluoro-N-(3- fluorobenzyl)-1,1′-biphenyl-2-carboxamide 97

* N-(indan-2-yl)-4′-methyl-N-(3- methylbenzyl)-1,1′-biphenyl-2-carboxamide 98

* N-(indan-2-yl)-3′-methoxy-N-(3- methylbenzyl)-1,1′-biphenyl-2-carboxamide 99

* N-(indan-2-yl)-2′-fluoro-N-(3- methylbenzyl)-1,1′-biphenyl-2-carboxamide 100

* N-(indan-2-yl)-4′-methyl-N-(2- methylbenzyl)-1,1′-biphenyl-2-carboxamide 101

* N-(indan-2-yl)-3-methoxy-N-(3- methoxybenzyl)-1,1′-biphenyl-2-carboxamide 102

* N-(indan-2-yl)-5-methoxy-N-(3- methoxybenzyl)-2-(5-methylthien-2-yl)benzamide 103

* N-(indan-2-yl)-4-methoxy-N-(3- methoxybenzyl)-1,1′-biphenyl-2-carboxamide 104

* N-(indan-2-yl)-5-methoxy-N-(3- methoxybenzyl)-2-thien-3- ylbenzamide105

* N-(indan-2-yl)-4-methoxy-N-(2- methylbenzyl)-1,1′-biphenyl-2-carboxamide 106

* N-(indan-2-yl)-4-methoxy-N-(3- methylbenzyl)-1,1′-biphenyl-2-carboxamide 107

* N-(indan-2-yl)-4-methoxy-N-(4- methylbenzyl)-1,1′-biphenyl-2-carboxamide 108

* N-(indan-2-yl)-N-(2- fluorobenzyl)-4-methoxy-1,1′-biphenyl-2-carboxamide 109

* N-(indan-2-yl)-N-(3- fluorobenzyl)-4-methoxy-1,1′-biphenyl-2-carboxamide 110

* N-(indan-2-yl)-N-(4- fluorobenzyl)-4-methoxy-1,1′-biphenyl-2-carboxamide 111

* N-(3,4-difluorobenzyl)-N-(indan- 2-yl)-4-methoxy-1,1′-biphenyl-2-carboxamide 112

* N-benzyl-N-(indan-2-yl)-3- fluoro-1,1′-biphenyl-2- carboxamide 113

* N-benzyl-N-(indan-2-yl)-3- methyl-1,1′-biphenyl-2- carboxamide 114

* N-benzyl-N-(indan-2-yl)-2- fluoro-6-(5-methylthien-2- yl)benzamide 115

* N-benzyl-N-(indan-2-yl)-2- methyl-6-(5-methylthien-2- yl)benzamide 116

* N-benzyl-N-(indan-2-yl)-4- methyl-1,1′-biphenyl-2- carboxamide 117

* N-benzyl-4-chloro-N-(indan-2- yl)-1,1′-biphenyl-2-carboxamide 118

* N-benzyl-N-(indan-2-yl)-5- methyl-2-thien-3-ylbenzamide 119

* N-benzyl-5-chloro-N-(indan-2- yl)-2-thien-3-ylbenzamide 120

* N-(indan-2-yl)-3-methyl-N-(2- methylbenzyl)-1,1′-biphenyl-2-carboxamide 121

* N-(indan-2-yl)-3-methyl-N-(3- methylbenzyl)-1,1′-biphenyl-2-carboxamide 122

* N-(indan-2-yl)-3-methyl-N-(4- methylbenzyl)-1,1′-biphenyl-2-carboxamide 123

* N-(indan-2-yl)-N-(2- fluorobenzyl)-3-methyl-1,1′-biphenyl-2-carboxamide 124

* N-(indan-2-yl)-N-(3- fluorobenzyl)-3-methyl-1,1′-biphenyl-2-carboxamide 125

* N-(indan-2-yl)-N-(4- fluorobenzyl)-3-methyl-1,1′-biphenyl-2-carboxamide 126

* N-(3,4-difluorobenzyl)-N-(indan- 2-yl)-3-methyl-1,1′-biphenyl-2-carboxamide 127

* N-(indan-2-yl)-N-(3- methoxybenzyl)-3-methyl-1,1′-biphenyl-2-carboxamide 128

* N-(indan-2-yl)-N-(4- methoxybenzyl)-3-methyl-1,1′-biphenyl-2-carboxamide 129

* N-(1,3-benzodioxol-5-ylmethyl)- N-(indan-2-yl)-3-methyl-1,1′-biphenyl-2-carboxamide 130

* N-(indan-2-yl)-3-methyl-N-(2- phenylethyl)-1,1′-biphenyl-2-carboxamide 131

* 4-chloro-N-(indan-2-yl)-N-(2- methylbenzyl)-1,1′-biphenyl-2-carboxamide 132

* 4-chloro-N-(indan-2-yl)-N-(3- methylbenzyl)-1,1′-biphenyl-2-carboxamide 133

4-chloro-N-(indan-2-yl)-N-(4- methylbenzyl)-1,1′-biphenyl-2- carboxamide134

* 4-chloro-N-(indan-2-yl)-N-(2- fluorobenzyl)-1,1′-biphenyl-2-carboxamide 135

* 4-chloro-N-(indan-2-yl)-N-(3- fluorobenzyl)-1,1′-biphenyl-2-carboxamide 136

* 4-chloro-N-(indan-2-yl)-N-(4- fluorobenzyl)-1,1′-biphenyl-2-carboxamide 137

* 4-chloro-N-(3,4-difluorobenzyl)- N-(indan-2-yl)-1,1′-biphenyl-2-carboxamide 138

* 4-chloro-N-(indan-2-yl)-N-(4- methoxybenzyl)-1,1′-biphenyl-2-carboxamide 139

* N-(1,3-benzodioxol-5-ylmethyl)- 4-chloro-N-(indan-2-yl)-1,1′-biphenyl-2-carboxamide 140

* 4-chloro-N-(indan-2-yl)-N-(3- methoxybenzyl)-1,1′-biphenyl-2-carboxamide 141

* 4-chloro-N-(indan-2-yl)-N-(2- phenylethyl)-1,1′-biphenyl-2-carboxamide 142

* N-benzyl-4-chloro-N-(4-hydroxy- 3,5-dimethylbenzyl)-1,1′-biphenyl-2-carboxamide 143

N-benzyl-N-{(1S,2S)-2-[4-(2- methoxyphenyl)piperazin-1-yl]-cyclohexyl}-1,1′-biphenyl-2- carboxamide 144

* N-benzyl-4-chloro-N-(2,3- dihydro-1-benzofuran-6-ylmethyl)-1,1′-biphenyl-2- carboxamide 145

* 4-chloro-N-(3-methoxybenzyl)- N-(2-phenylethyl)-1,1′-biphenyl-2-carboxamide 146

* N-benzyl-4-chloro-N-(1- naphthylmethyl)-1,1′-biphenyl-2- carboxamide147

* N-benzyl-N-(4-hydroxy-3,5- dimethylbenzyl)-2-(5-methylthien-2-yl)benzamide 148

* N-benzyl-N-[4- (difluoromethoxy)benzyl]-2-(5-methylthien-2-yl)benzamide 149

* N-benzyl-N-(2-chloro-4- hydroxybenzyl)-2-(5-methylthien-2-yl)benzamide 150

* N-benzyl-N-(4-hydroxy-3,5- dimethylbenzyl)-1,1′-biphenyl-2-carboxamide 151

* N-benzyl-N-[4- (difluoromethoxy)benzyl]-1,1′- biphenyl-2-carboxamide152

N-benzyl-2-(5-methylthien-2-yl)- N-[3-(trifluoromethyl)benzyl] benzamide

TABLE II LC CMP# STRUCTURE IUPAC Name (min.) MW LCMS 153

N-benzyl-N-(2- methylbenzyl)-2-(1H-pyrrol- 1-yl)benzamide 2.27 380.49380.19 154

N-(2-methoxybenzyl)-N-(2- methylbenzyl)-2-(1H-pyrrol- 1-yl)benzamide2.27 410.51 410.20 155

N-(2,2-diphenylethyl)-N-(2- methylbenzyl)-2-(1H-pyrrol- 1-yl)benzamide2.38 470.61 470.24 156

N-(2,4-difluorobenzyl)-N-(2- methoxybenzyl)-2-(1H- pyrrol-1-yl)benzamide2.26 432.47 432.16 157

N-(2,4-difluorobenzyl)-N- (2,2-diphenylethyl)-2-(1H-pyrrol-1-yl)benzannde 2.36 492.57 492.20 158

N-(2,6-dichlorobenzyl)-N-(2- methoxybenzyl)-2-(1H- pyrrol-1-yl)benzamide2.28 465.38 464.11 159

N-benzyl-N-(1,1′-biphenyl-2- ylmethyl)-2-(1H-pyrrol-1- yl)benzamide 2.34442.56 442.20 160

N-(1,1′-biphenyl-2-ylmethyl)- N-(2-methoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 2.35 472.59 472.22 161

N-(1,1′-biphenyl-2-ylmethyl)- N-(2-phenylbutyl)-2-(1H-pyrrol-1-yl)benzamide 2.46 484.64 484.25 162

N-(1,1′-biphenyl-2-ylmethyl)- N-(2,2-diphenylethyl)-2-(1H-pyrrol-1-yl)benzamide 2.45 532.68 532.25 163

N-(1,1′-biphenyl-2-ylmethyl)- N-(cyclohexylmethyl)-2-(1H-pyrrol-1-yl)benzamide 2.01 448.61 448.25 164

N-(2,4-dimethoxybenzyl)-N- (4-fluorobenzyl)-2-(1H- pyrrol-1-yl)benzamide1.3 444.50 444.18 165

N-(2-methoxybenzyl)-N-(4- methylbenzyl)-2-(1H-pyrrol- 1-yl)benzamide1.34 410.51 410.20 166

N-(3-methoxybenzyl)-N-(4- methylbenzyl)-2-(1H-pyrrol- 1-yl)benzamide1.33 410.51 410.20 167

N-(4-methoxybenzyl)-N-(4- methylbenzyl)-2-(1H-pyrrol- 1-yl)benzamide1.33 410.51 410.20 168

N-(4-methylbenzyl)-2-(1H- pyrrol-1-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide 1.37 464.49 464.17 169

N-(2,4-dimethoxybenzyl)-N- (4-methylbenzyl)-2-(1H- pyrrol-1-yl)benzamide1.33 440.54 440.21 170

N-(3,5-dimethoxybenzyl)-N- (4-methylbenzyl)-2-(1H- pyrrol-1-yl)benzamide1.33 440.54 440.21 171

N-(4-chlorobenzyl)-N-(2- methoxybenzyl)-2-(1H- pyrrol-1-yl)benzamide1.34 430.93 430.14 172

N-(4-chlorobenzyl)-N-(3- methoxybenzyl)-2-(1H- pyrrol-1-yl)benzamide1.33 430.93 430.14 173

N-(4-chlorobenzyl)-N-(4- methoxybenzyl)-2-(1H- pyrrol-1-yl)benzamide1.34 430.93 430.14 174

N-(1,3-benzodioxol-5- ylmethyl)-N-(4- chlorobenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.33 444.92 444.12 175

N-(4-chlorobenzyl)-2-(1H- pyrrol-1-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide 1.37 484.90 484.12 176

N-(4-chlorobenzyl)-N-(2,4- dimethoxybenzyl)-2-(1H- pyrrol-1-yl)benzamide1.33 460.96 460.16 177

N-(2-methoxybenzyl)-2-(1H- pyrrol-1-yl)-N-[4- (trifluoromethyl)benzyl]benzamide 1.33 464.49 464.17 178

N-(4-methoxybenzyl)-2-(1H- pyrrol-1-yl)-N-[4- (trifluoromethyl)benzyl]benzamide 1.33 464.49 464.17 179

N-(2,4-dimethoxybenzyl)-2- (1H-pyrrol-1-yl)-N-[4- (trifluoromethyl)benzyl]benzamide 1.33 494.51 494.18 180

N-(3,5-dimethoxybenzyl)-2- (1H-pyrrol-1-yl)-N-[4- (trifluoromethyl)benzyl]benzamide 1.32 494.51 494.18 181

N-(2-methoxybenzyl)-2-(1H- pyrrol-1-yl)-N-[2,4-(difluoro)benzyl]benzamide 1.3 432.47 432.16 182

N-(2,4-difluorobenzyl)-N-(4- methoxybenzyl)-2-(1H- pyrrol-1-yl)benzamide1.3 432.47 432.16 183

N-(2,4-difluorobenzyl)-N- (2,4-dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.3 462.49 462.18 184

N-(2,4-dichlorobenzyl)-N-(2- methoxybenzyl)-2-(1H- pyrrol-1-yl)benzamide1.38 465.38 464.11 185

N-(2,4-dichlorobenzyl)-N-(3- methoxybenzyl)-2-(1H- pyrrol-1-yl)benzamide1.37 465.38 464.11 186

N-(2,4-dichlorobenzyl)-N-(4- methoxybenzyl)-2-(1H- pyrrol-1-yl)benzamide1.37 465.38 464.11 187

N-(1,3-benzodioxol-5- ylmethyl)-N-(2,4- dichlorobenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.35 479.36 478.09 188

N-(2,4-dichlorobenzyl)-2- (1H-pyrrol-1-yl)-N-[4-(trifluoromethoxy)benzyl]benzamide 1.4 519.35 518.08 189

N-(2,4-dichlorobenzyl)-N- (2,4-dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.36 495.40 494.12 190

N-(2,4-dichlorobenzyl)-N- (3,5-dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.37 495.40 494.12 191

N-(2-chloro-4-fluorobenzyl)- N-(3-methoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.33 448.92 448.14 192

N-(2-chloro-4-fluorobenzyl)- N-(4-methoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.14 448.92 448.14 193

N-(1,3-benzodioxol-5- ylmethyl)-N-(2-chloro-4-fluorobenzyl)-2-(1H-pyrrol-1- yl)benzamide 1.32 462.91 462.11 194

N-(2-chloro-4-fluorobenzyl)- N-(2,4-dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.33 478.95 478.15 195

N-(2-chloro-4-fluorobenzyl)- N-(3,5-dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.32 478.95 478.15 196

N-(2,3-difluorobenzyl)-N- (2,4-dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.32 462.49 462.18 197

N-(3-chloro-2-fluorobenzyl)- N-(2,4-dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.35 478.95 478.15 198

N-(3-chloro-2-fluorobenzyl)- N-(3,5-dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.35 478.95 478.15 199

N-[(5-chlorothien-2- yl)methyl]-N-(4- methoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.34 436.96 436.10 200

N-[(5-chlorothien-2- yl)methyl]-N-(2,4- dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.34 466.99 466.11 201

N-[(5-chlorothien-2- yl)methyl]-N-(3,5- dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.34 466.99 466.11 202

N-(2,5-difluorobenzyl)-N- (2,4-dimethoxybenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.31 462.49 462.18 203

N-(2,4-difluorobenzyl)-N-[2- (2-fluorophenyl)ethyl]-2-(1H-pyrrol-1-yl)benzamide 1.34 434.46 434.16 204

N-(indan-2-yl)-N-(3- methylbenzyl)-2-(1H-pyrrol- 1-yl)benzamide 1.19406.53 406.20 205

N-(indan-2-yl)-N-(4- methylbenzyl)-2-(1H-pyrrol- 1-yl)benzamide 1.34406.53 406.20 206

N-(indan-1-yl)-2-(1H-pyrrol- 1-yl)-N-[4- (trifluoromethyl)benzyl]benzamide 1.33 460.50 460.18 207

N-(2,3-dihydro-1H-inden-1- yl)-N-(4-methylbenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.35 406.53 406.20 208

N-Indan-2-yl-N-(4-methyl- benzyl)-2-pyrrol-1-yl- benzamide 1.32 406.53406.20 209

N-(4-chlorobenzyl)-N-(2,3- dihydro-1H-inden-1-yl)-2-(1H-pyrrol-1-yl)benzamide 1.35 426.95 426.15 210

N-(4-chlorobenzyl)-N-(indan- 2-yl)-2-(1H-pyrrol-1- yl)benzamide 1.34426.95 426.15 211

N-(indan-2-yl)-2-(1H-pyrrol- 1-yl)-N-[4-(trifluoromethyl)benzyl]benzamide 1.31 460.50 460.18 212

N-(2,3-dihydro-1H-inden-1- yl)-N-(3,5-dimethylbenzyl)-2-(1H-pyrrol-1-yl)benzamide 1.38 420.55 420.22 213

N-(indan-2-yl)-N-(3,5- dimethylbenzyl)-2-(1H- pyrrol-1-yl)benzamide 1.18420.55 420.22 214

N-(indan-2-yl)-N-(1- naphthylmethyl)-2-(1H- pyrrol-1-yl)benzamide 1.36442.56 442.20 215

N-(2,3-dihydro-1H-inden-1- yl)-N-(2-naphthylmethyl)-2-(1H-pyrrol-1-yl)benzamide 1.36 442.56 442.20 216

N-(indan-2-yl)-N-(2- naphthylmethyl)-2-(1H- pyrrol-1-yl)benzamide 1.36442.56 442.20

TABLE III CMP Ca2+ LC- # STRUCTURE IUPAC NAME Mob. MS NMR 217

N-benzyl-N-(4-hydroxy-3,5- dimethylbenzyl)-2-methoxy- 1-naphthamide *423 ¹H-NMR (δ, CDCl₃): 7.85(dd, J=9, 5Hz, 1H), 7.74-7.9(m, 2H), 7.47(d,J=7Hz, 1H), 7.06-7.42(m, 9H), 7.04(s, 1H), 6.60(s, 1H), 4.93(d, J=15Hz,1H), 4.70(d, J=15Hz, 1H), 4.03-4.18(m, 2H), 3.98(s, 3H, OMe), 2.28(s,3H, Me), 2.11(s, 3H, Me). 218

2-Methoxy-naphthalene-1- carboxylic acid(2-fluoro-benzyl)-indan-2-yl-amide 219

2-Methoxy-naphthalene-1- carboxylic acid(3,4-difluoro-benzyl)-indan-2-yl-amide 444 1H-NMR (δ, CDCl3): 7.88(1H, d, J=9Hz),7.81(d, J=8Hz, 1H), 7.71(d, J=8Hz, 1H), 7.52(t, J=7Hz, 1H), 7.54-6.99(m,9H), 5.30(d, J=16Hz, 1H), 4.59(t, J=8Hz, 1H), 7.40(d, J=16Hz, 1H),4.06(s, 3H, OMe), 3.00(dd, J=8Hz, 1H), 2.87(d, J=8Hz, 2H), 2.74(d,J=8Hz, 1H). 220

2-Methoxy-naphthalene-1- carboxylic acid indan-2-yl- phenethyl-amide *221

2-Methoxy-naphthalene-1- carboxylic acid(3-methyl-benzyl)-indan-2-yl-amide * 422 1H-NMR (δ, CDCl3): 7.85(1H, d, J=9Hz),7.81-7.70(m, 2H), 7.50(t, J=7Hz, 1H), 7.45-6.80(m, 10H), 5.19(d, J=16Hz,1H), 4.55-4.65t(m, 2H), 4.04(s, 3H, OMe), 2.92-3.05(m, 2H), 2.86(dd,J=16, 8Hz, 1H), 2.65(dd, J=16, 8Hz, 1H), 2.38(s, 3H, Me). 222

2-Methoxy-naphthalene-1- carboxylic acid(4-methoxy-benzyl)-indan-2-yl-amide 223

2-Methoxy-naphthalene-1- carboxylic acid(4-methyl-benzyl)-indan-2-yl-amide * 422 224

2-Methoxy-naphthalene-1- carboxylic acid(2-methyl-benzyl)-indan-2-yl-amide * 225

2-Methoxy-naphthalene-1- carboxylic acid(4-fluoro-benzyl)-indan-2-yl-amide 426. 226

2-Methoxy-naphthalene-1- carboxylic acid(3-fluoro-benzyl)-indan-2-yl-amide 426 1H-NMR (δ, CDCl3): 7.88(d, J=9Hz, 1H),7.81(d, J=8Hz, 1H), 7.75(d, J=8Hz, 1H), 7.52(t, J=7Hz, 1H), 7.39(t,J=8Hz, 1H), 7.25-7.33(m, 4H), 6.94-7.15(m, 5H), 5.34(d, J=16Hz, 1H),4.61(t, J=16Hz, 1H), 4.50(d, J=16Hz, 1H), 4.07(s, 3H, OMe), 3.02(dd,J=16, 8Hz, 1H), 2.89(dd, J=8, 4Hz, 1H), 2.72(dd, J=16, 8Hz, 1H). 227

2-Methoxy-naphthalene-1- carboxylic acid(3-methoxy-benzyl)-indan-2-yl-amide 438 228

2-Methoxy-naphthalene-1- carboxylic acid benzo[1,3]dioxol-5-ylmethyl-indan-2-yl-amide * 452 1H-NMR (δ, CDCl3): 7.68-8.12(m, 4H), 7.01-7.56(m,8H), 6.78(d, J=4Hz, 1H), 5.97(dd, J=9, 1HZ, 1H), 5.19(d, J=16Hz, 1H),4.57(t, J=8Hz, 1H), 4.50(d, J=16Hz, 1H), 4.04(s, #H, OMe), 2.95-3.07(m,2H), 2.86(dd, J=16, 8Hz, 1H), 2.69(dd, J=16, 8Hz, 1H). 229

2-Methyl-naphthalene-1- carboxylic acid(2-methyl-benzyl)-indan-2-yl-amide 406 230

2-Methyl-naphthalene-1- carboxylic acid(3-methyl-benzyl)-indan-2-yl-amide * 406. 231

2-Methyl-naphthalene-1- carboxylic acid(4-methyl-benzyl)-indan-2-yl-amide 406 232

2-Methyl-naphthalene-1- carboxylic acid(2-fluoro-benzyl)-indan-2-yl-amide 426 1H-NMR (δ, CDCl3): 7.87(d, J=9Hz, 1H),7.70-7.83(m, 3H), 7.53(t, J=7Hz, 1H), 7.13-7.41(m, 5H), 6.96-7.05(m,4H), 5.31(d, J=15Hz, 1H), 4.72(d, J=15Hz, 1H), 4.61(t, J=9Hzx, 1H),4.06(d, J=1Hz, 3H, OMe), 3.07(dd, J=16, 9Hx, 1H) 2.94(dd, J=16, 9Hz,1H), 2.85(dd, J=16, 8Hz, 1h), 2.66(DD, j=16, 8Hz, 1H). 233

2-Methyl-naphthalene-1- carboxylic acid(3-fluoro-benzyl)-indan-2-yl-amide 234

2-Methyl-naphthalene-1- carboxylic acid(4-fluoro-benzyl)-indan-2-yl-amide 410 1H-NMR (δ, CDCl3): 7.85-7.73(m, 3H),7.44-7.55(m, 2H), 7.33-7.40(m, 2H), 7.01-7.25(m, 6H), 6.83-6.86(m, 1H),4.99(d, J=15Hz, 1H), 4.70(d, J=15Hz, 1H), 4.48(t, J=7Hz, 1H),2.96-3.02(dd, J=16, 7Hz, 2H), 2.90(dd, J=16, 8Hz, 1H), 2.70(dd, J=16,8Hz, 1H), 2.56(S, 3h, Me). 235

2-Methyl-naphthalene-1- carboxylic acid indan-2-yl- phenethyl-amide *422 1H-NMR (δ, CDCl3): 7.86(d, J=10Hx, 1H), 7.79(d, J=8Hz, 1H), 7.71(t,J=8Hz, 1H), 7.50(m, 1H), 7.20-7.39(m, 7H), 6.97-7.14(m, 4H), 4.44(t,J=8Hz, 1H), 4.00(s, 3H, OMe), 3.73(m, 2H), 3.24-3.31(m, 1H),3.10-3.19(m, 1H), 2.92-3.09(m, 1H), 2.75(dd, J=8Hz, 1H). 236

Naphthalene-1-carboxylic acid benzyl-(2-chloro-4-hydroxy-benzyl)-amide * 237

2-Hydroxy-naphthalene-1- carboxylic acid(2-fluoro-benzyl)-indan-2-yl-amide * 238

2-Hydroxy-naphthalene-1- carboxylic acid(4-methyl-benzyl)-indan-2-yl-amide * 239

2-Phenyl-naphthalene-1- carboxylic acid(2-fluoro-benzyl)-indan-2-yl-amide * 240

2-Phenyl-naphthalene-1- carboxylic acid(4-methyl-benzyl)-indan-2-yl-amide * 241

2-(5-Methyl-thiopben-2-yl)- naphthalene-1-carboxylicacid(2-fluoro-benzyl)-indan- 2-yl-amide * 242

2-Methoxy-naphthalene-1- carboxylic acid(4- carbamoyl-3-hydroxy-benzyl)-indan-2-yl-amide 243

4-{[Indan-2-yl-(2-methoxy- naphthalene-1-carbonyl)-amino]-methyl}-benzoic acid

Example 11 Pharmaceutical Preparations of Oral and IntravenousAdministration

A. Tablets containing a C5a antagonist and an anti-arthritic agent whichis not a C5a receptor antagonist can be prepared as illustrated below:

Ingredient Amount C5a receptor antagonist 5 mg-500 mg C5areceptor-inactive therapeutic 1 mg-500 mg agent diluent, binder,disintigrant, lubricant excipients q.s. 200-400 mg.B. Tablets containing a C5a receptor antagonist as the only activeingredient can be prepared as illustrated below:

Ingredient mg mg C5a receptor antagonist 10 50 MicrocrystallineCellulose 70.4 352 Grannular Mannitol 15.1 75.5 Croscarmellose Sodium3.0 15.0 Colloidal Silicon Dioxide 0.5 2.5 Magnesium Stearate(Impalpable Powder) 1.0 5.0 Total (mg) 100 500C. Tablets containing a C5a receptor antagonist and a C5a receptorinactive agent may be prepared as follows:

Ingredient mg mg C5a receptor antagonist 10 25 C5a receptor inactivetherapeutic agent 10 25 Microcrystalline Cellulose 40 100 Modified foodcorn starch 1.05 4.25 Magnesium stearate 1.25 0.5D. Intravenous formulations containing a C5a receptor antagonist and aC5a receptor inactive agent may be prepared as follows:

Ingredient Amount C5a receptor antagonist 0.5-10 mg C5a receptorinactive therapeutic agent 0.5-10 mg Sodium Citrate 5-50 mg Citric Acid1-15 mg Sodium Chloride 1-8 mg Water for Injection to 1.0 literE. Oral suspensions containing a C5a receptor antagonist and a C5areceptor inactive agent may be prepared as follows:

Ingredient Amount per 5 ml dose C5a receptor antagonist 5-100 mg C5areceptor inactive therapeutic agent 5-100 mg Polyvinylpyrrolidone 150 mgPoly oxyethylene sorbitan monolaurate 25 mg Benzoic Acid 10 mg to 5 mLwith sorbitol solution (70%)

Example 12 Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

For example, alpha-Napthoic acid, [1-¹⁴C] (Available from AmericanRadiolabeled Chemicals, St. Louis, Mo., Product No. ARC-153) may be usedas a starting material in the to obtain many of the biarylamidesprovided herein using the method shown in Scheme 2.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound of theinvention as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

Example 13 Receptor Autoradiography

Receptor autoradiography (receptor mapping) is carried out in vitro asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York, using radiolabeledcompounds of the invention prepared as described in the precedingExamples.

Example 14 Assay for C5a Receptor Mediated Chemotaxis

This assay is a standard assay of C5a receptor mediated chemotaxis.

Human promonocytic U937 cells or purified human or non-human neutrophilsare treated with dibutyryl cAMP for 48 hours prior to performing theassay. Human neutrophils or those from another mammalian species areused directly after isolation. The cells are pelleted and resuspended inculture media containing 0.1% fetal bovine serum (FBS) and 10 ug/mlcalcein AM (a fluorescent dye). This suspension is then incubated at 37°C. for 30 minutes such that the cells take up the fluorescent dye. Thesuspension is then centrifuged briefly to pellet the cells, which arethen resuspended in culture media containing 0.1% FBS at a concentrationof approximately 3×10⁶ cells/mL. Aliquots of this cell suspension aretransferred to clean test tubes, which contain vehicle (1% DMSO) orvarying concentrations of a compound of interest, and incubated at roomtemperature for at least 30 minutes. The chemotaxis assay is performedin CHEMO TX 101-8, 96 well plates (Neuro Probe, Inc. Gaithersburg, Md.).The bottom wells of the plate are filled with medium containing 0-10 nMof C5a, preferably derived from the same species of mammal as are theneutrophils or other cells (e.g., human C5a for the human U937 cells).The top wells of the plate are filled with cell suspensions (compound orvehicle-treated). The plate is then placed in a tissue culture incubatorfor 60 minutes. The top surface of the plate is washed with PBS toremove excess cell suspension. The number of cells that have migratedinto the bottom well is then determined using a fluorescence reader.Chemotaxis index (the ratio of migrated cells to total number of cellsloaded) is then calculated for each compound concentration to determinean IC₅₀ value.

As a control to ensure that cells retain chemotactic ability in thepresence of the compound of interest, the bottom wells of the plate maybe filled with varying concentrations chemo-attractants that do notmediate chemotaxis via the C5a receptor (e.g., zymosan-activated serum(ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or leukotriene B4(LTB4)), rather than C5a, under which conditions the compounds providedherein preferably do not inhibit chemotaxis.

Preferred compounds exhibit IC₅₀ values of less than 1 μM in the aboveassay for C5a receptor mediated chemotaxis.

Example 15 Expression of a C5a Receptor

A human C5a receptor cDNA is obtained by PCR using 1) a forward primeradding a Kozak ribosome binding site and 2) a reverse primer that addedno additional sequence, and 3) an aliquot of a Stratagene Human FetalBrain cDNA library as template. The sequence of the resulting PCRproduct is as described by Gerard and Gerard, (1991) Nature 349:614-17.The PCR product is subcloned into the cloning vector pCR-Script AMP(STRATAGENE, La Jolla, Calif.) at the Srf I site. It is then excisedusing the restriction enzymes EcoRI and NotI and subcloned in theappropriate orientation for expression into the baculoviral expressionvector pBacPAK 9 (CLONTECH, Palo Alto, Calif.) that has been digestedwith EcoRI and NotI.

Example 16 Baculoviral Preparations for C5a Expression

The human C5a (hC5a) receptor baculoviral expression vector isco-transfected along with BACULOGOLD DNA (BD PharMingen, San Diego,Calif.) into Sf9 cells. The Sf9 cell culture supernatant is harvestedthree days post-transfection. The recombinant virus-containingsupernatant is serially diluted in Hink's TNM-FH insect medium (JRHBiosciences, Lenexa, Kans.) supplemented Grace's salts and with 4.1 mML-Gln, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10%heat-inactivated fetal bovine serum (hereinafter “insect medium”) andplaque assayed for recombinant plaques. After four days, recombinantplaques are selected and harvested into 1 ml of insect medium foramplification. Each 1 ml volume of recombinant baculovirus (at passage0) is used to infect a separate T25 flask containing 2×10⁶ Sf9 cells in5 mls of insect medium. After five days of incubation at 27° C.,supernatant medium is harvested from each of the T25 infections for useas passage 1 inoculum.

Two of seven recombinant baculoviral clones are then chosen for a secondround of amplification, using 1 ml of passage 1 stock to infect 1×10⁸cells in 100 ml of insect medium divided into 2 T175 flasks. Forty-eighthours post infection, passage 2 medium from each 100 ml prep isharvested and plaque assayed for titer. The cell pellets from the secondround of amplification are assayed by affinity binding as describedbelow to verify recombinant receptor expression. A third round ofamplification is then initiated using a multiplicity of infection of 0.1to infect a liter of Sf9 cells. Forty hours post-infection thesupernatant medium is harvested to yield passage 3 baculoviral stock.

The remaining cell pellet is assayed for affinity binding using the“Binding Assays” essentially as described by DeMartino et al. (1994) J.Biol. Chem. 269:14446-50 at page 14447, adapted as follows. Radioligandis 0.005-0.500 nM [¹²⁵I]C5a (human recombinant; New England NuclearCorp., Boston, Mass.); the hC5a receptor-expressing baculoviral cellsare used instead of 293 cells; the assay buffer contains 50 mM Hepes pH.7.6, 1 mM CaCl₂, 5 mM MgCl₂, 0.1% BSA, pH 7.4, 0.1 mM bacitracin, and100 KIU/ml aprotinin; filtration is carried out using GF/C WHATMANfilters (presoaked in 1.0% polyethyeneimine for 2 hours prior to use);and the filters are washed twice with 5 mLs cold binding buffer withoutBSA, bacitracin, or aprotinin.

Titer of the passage 3 baculoviral stock is determined by plaque assayand a multiplicity of infection, incubation time course, binding assayexperiment is carried out to determine conditions for optimal receptorexpression. A multiplicity of infection of 0.1 and a 72-hour incubationwere the best infection parameters found for hC5a receptor expression inup to 1-liter Sf9 cell infection cultures.

Example 17 Baculoviral Infections

Log-phase Sf9 cells (INVITROGEN Corp., Carlsbad, Calif.) are infectedwith one or more stocks of recombinant baculovirus followed by culturingin insect medium at 27° C. Infections are carried out either only withvirus directing the expression of the hC5a receptor or with this virusin combination with three G-protein subunit-expression virus stocks: 1)rat G□_(i2) G-protein-encoding virus stock (BIOSIGNAL #V5J008), 2)bovine b1 G-protein-encoding virus stock (BIOSIGNAL #V5H012), and 3)human g2 G-protein-encoding virus stock (BIOSIGNAL #V6B003), all ofwhich may be obtained from BIOSIGNAL Inc. (Montreal, Canada).

The infections are conveniently carried out at a multiplicity ofinfection of 0.1:1.0:0.5:0.5. At 72 hours post-infection, a sample ofcell suspension is analyzed for viability by trypan blue dye exclusion,and the remaining Sf9 cells are harvested via centrifugation (3000rpm/10 minutes/4° C.).

Example 18 Purified Recombinant Insect Cell Membranes

Sf9 cell pellets are resuspended in homogenization buffer (10 mM HEPES,250 mM sucrose, 0.5 ug/ml leupeptin, 2 ug/ml Aprotinin, 200 uM PMSF, and2.5 mM EDTA, pH 7.4) and homogenized using a POLYTRON homogenizer(setting 5 for 30 seconds). The homogenate is centrifuged (536×g/10minutes/4° C.) to pellet the nuclei. The supernatant containing isolatedmembranes is decanted to a clean centrifuge tube, centrifuged(48,000×g/30 minutes, 4° C.) and the resulting pellet resuspended in 30ml homogenization buffer. This centrifugation and resuspension step isrepeated twice. The final pellet is resuspended in ice cold Dulbecco'sPBS containing 5 mM EDTA and stored in frozen aliquots at −80° C. untilneeded. The protein concentration of the resulting membrane preparation(hereinafter “P2 membranes”) is conveniently measured using a Bradfordprotein assay (Bio-Rad Laboratories, Hercules, Calif.). By this measure,a 1-liter culture of cells typically yields 100-150 mg of total membraneprotein.

Example 19 Radioligand Binding Assays

Purified P2 membranes, prepared by the method given above, areresuspended by Dounce homogenization (tight pestle) in binding buffer(50 mM Hepes pH. 7.6, 120 mM NaCl, 1 mM CaCl₂, 5 mM MgCl₂, o.1% BSA, pH7.4, 0.1 mM bacitracin, 100 KIU/ml aprotinin).

For saturation binding analysis, membranes (5-50 μg) are added topolypropylene tubes containing 0.005-0.500 nM [¹²⁵I]C5a (human(recombinant), New England Nuclear Corp., Boston, Mass.). Nonspecificbinding is determined in the presence of 300 nM hC5a (Sigma ChemicalCo., St. Louis, Mo.) and accounts for less than 10% of total binding.For evaluation of guanine nucleotide effects on receptor affinity, GTPγSis added to duplicate tubes at the final concentration of 50 μM.

For competition analysis, membranes (5-50 μg) are added to polypropylenetubes containing 0.030 nM [¹²⁵I]C5a (human). Non-radiolabeled displacersare added to separate assays at concentrations ranging from 10⁻¹⁰ M to10⁻⁵ M to yield a final volume of 0.250 mL. Nonspecific binding isdetermined in the presence of 300 nM hC5a (Sigma Chemical Co., St.Louis, Mo.) and accounts for less than 10% of total binding. Following a2-hour incubation at room temperature, the reaction is terminated byrapid vacuum filtration. Samples are filtered over presoaked (in 1.0%polyethyleneimine for 2 hours prior to use) GF/C WHATMAN filters andrinsed 2 times with 5 mLs cold binding buffer without BSA, bacitracin,or aprotinin. Remaining bound radioactivity is quantified by gammacounting. K_(I) and Hill coefficient (“nH”) are determined by fittingthe Hill equation to the measured values with the aid of SIGMAPLOTsoftware (SPSS Inc., Chicago, Ill.).

Example 20 Agonist-induced GTP Binding

Agonist-stimulated GTP-gamma ³⁵S binding (“GTP binding”) activity can beused to identify agonist and antagonist compounds and to differentiateneutral antagonist compounds from those that possess inverse agonistactivity. This activity can also be used to detect partial agonismmediated by antagonist compounds. A compound being analyzed in thisassay is referred to herein as a “test compound.” Agonist-stimulated GTPbinding activity is measured as follows: Four independent baculoviralstocks (one directing the expression of the hC5a receptor and threedirecting the expression of each of the three subunits of aheterotrimeric G-protein) are used to infect a culture of Sf9 cells asdescribed in Example 17.

Agonist-stimulated GTP binding on purified membranes (prepared asdescribed in Example 18) is assessed using hC5a (Sigma Chemical Co., St.Louis, Mo.) as agonist in order to ascertain that thereceptor/G-protein-alpha-beta-gamma combination(s) yield a functionalresponse as measured by GTP binding.

P2 membranes are resuspended by Dounce homogenization (tight pestle) inGTP binding assay buffer (50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgCl2, 2mM EGTA, 0.1% BSA, 0.1 mM bacitracin, 100 KIU/mL aprotinin, 5 μM GDP)and added to reaction tubes at a concentration of 30 μg protein/reactiontube. After adding increasing doses of the agonist hC5a atconcentrations ranging from 10⁻¹² M to 10⁻⁶ M, reactions are initiatedby the addition of 100 pM GTP-gamma ³⁵S. In competition experiments,non-radiolabeled test compounds are added to separate assays atconcentrations ranging from 10⁻¹⁰ M to 10⁻⁵ M along with 10 nM hC5a toyield a final volume of 0.25 mL.

Neutral antagonists are those test compounds that reduce theC5a-stimulated GTP binding activity towards, but not below, baseline(the level of GTP bound by membranes in this assay in the absence ofadded C5a or other agonist and in the further absence of any testcompound).

In contrast, in the absence of added C5a certain preferred compoundswill reduce the GTP binding activity of the receptor-containingmembranes below baseline, and are thus characterized as inverseagonists. If a test compound that displays antagonist activity does notreduce the GTP binding activity below baseline in the absence of the C5aagonist, it is characterized as a neutral antagonist.

An antagonist test compound that elevates GTP binding activity abovebaseline in the absence of added hC5a in this GTP binding assay ischaracterized as having partial agonist activity. Preferred antagonistcompounds do not elevate GTP binding activity under such conditions morethan 10%, 5% or 2% above baseline.

Following a 60-minute incubation at room temperature, the reactions areterminated by vacuum filtration over GF/C filters (pre-soaked in washbuffer, 0.1% BSA) followed by washing with ice-cold wash buffer (50 mMTris pH 7.0, 120mM NaCl). The amount of receptor-bound (and therebymembrane-bound) GTP-gamma ³⁵S is determined by measuring the boundradioactivity, preferably by liquid scintillation spectrometry of thewashed filters. Non-specific binding is determined using 10 mM GTP-gamma³⁵S and typically represents less than 5 percent of total binding. Datais expressed as percent above basal (baseline). The results of these GTPbinding experiments may be conveniently analyzed using SIGMAPLOTsoftware.

Example 21 Calcium Mobilization Assays

A. Response to C5a

U937 cells are grown in differentiation media (1 mM dibutyrl cAMP inRPMI 1640 medium containing 10% fetal bovine serum) for 48 hrs at 37° C.then reseeded onto 96-well plates suitable for use in a FLIPR™ PlateReader (Molecular Devices Corp., Sunnyvale, Calif.). Cells are grown anadditional 24 hours (to 70-90% confluence) before the assay. The cellsare then washed once with Krebs Ringer solution. FLUO-3 calciumsensitive dye (Molecular Probes, Inc. Eugene, Oreg.) is added to 10μg/mL and incubated with the cells at room temperature for 1 to 2 hours.The 96 well plates are then washed to remove excess dye. Fluorescenceresponses, measured by excitation at 480 nM and emission at 530 nM, aremonitored upon the addition of human C5a to the cells to a finalconcentration of 0.01-30.0 nM, using the FLIPR™ device (MolecularDevices). Differentiated U937 cells typically exhibit signals of5,000-50,000 Arbitrary Fluorescent Light Units in response to agoniststimulation.

B. Assays for Determination of ATP Responses

Differentiated U937 cells (prepared and tested as described above under“A. Response to C5a”) are stimulated by the addition of ATP (rather thanC5a) to a final concentration of 0.01 to 30 μM. This stimulationtypically triggers a signal of 1,000 to 12,000 arbitrary fluorescencelight units. Certain preferred compounds produce less than a 10%, lessthan a 5%, or less than a 2% alteration of this calcium mobilizationsignal when this control assay is carried out in the presence of thecompound, as compared to the signal when the assay is performed in theabsence of the compound.

C. Assays for the Identification of Receptor Modulatory Agents:Antagonists and Agonists

The calcium mobilization assay described above may be readily adaptedfor identifying test compounds that have agonist or antagonist activityat the human C5a receptor.

For example, in order to identify antagonist compounds, differentiatedU937 cells are washed and incubated with Fluo-3 dye as described above.One hour prior to measuring the fluorescence signal, a subset of thecells is incubated with 1 μM of at least one compound to be tested. Thefluorescence response upon the subsequent addition of 0.3 nM (finalconcentration) human recombinant C5a is monitored using the FLIPR™ platereader. Antagonist compounds elicit at least a 2-fold decrease in thefluorescence response relative to that measured in the presence of humanC5a alone. Preferred antagonist compounds elicit at least a 5-fold,preferably at least a 10-fold, and more preferably at least a 20-folddecrease in the fluorescence response relative to that measured in thepresence of human C5a alone. Agonist compounds elicit an increase influorescence without the addition of C5a, which increase will be atleast partially blocked by a known C5a receptor antagonist.

Example 22 Assays to Evaluate Agonist Activity of Small Molecule C5aReceptor Antagonists

Preferred compounds provided herein are C5a receptor antagonists that donot possess significant (e.g., greater than 5%) agonist activity in anyof the C5a mediated functional assays discussed herein. Specifically,this undesired agonist activity can be evaluated, for example, in theGTP binding assay of Example 20, by measuring small molecule mediatedGTP binding in the absence of the natural agonist, C5a. Similarly, in acalcium mobilization assay (e.g., that of Example 21), a small moleculecompound can be directly assayed for the ability of the compound tostimulate calcium levels in the absence of the natural agonist, C5a. Thepreferred extent of C5a agonist activity exhibited by compounds providedherein is less than 10%, more preferably less than 5% and mostpreferably less than 2% of the response elicited by the natural agonist,C5a.

The foregoing description is illustrative thereof, and it will beunderstood that variations and modifications can be effected withoutdeparting from the scope or spirit of the invention as set forth in thefollowing Claims.

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein Ar¹ is optionallysubstituted phenyl having at least one optionally substitutedheterocyclic substituent attached thereto at the 2-position relative tothe point of attachment, wherein the heterocyclic substituent is chosenfrom imidazoloyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl andpyrimidinyl; R¹ is optionally substituted cycloalkyl, optionallysubstituted (cycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl,optionally substituted (aryl)alkyl, optionally substituted aryl,optionally substituted heteroaryl having about 5 to 7 ring atoms andbetween 1 and 3 ring heteroatoms selected from N, O, and S, oroptionally substituted (aryl)alkyl, wherein the aryl portion is fused toa 5- to 7-membered saturated or partially unsaturated ring that (a) has0, 1 or 2 ring atoms independently chosen from N, O and S, withremaining ring atoms being carbon, and (b) is substituted with from 0 to2 substituents independently chosen from halogen, alkyl and alkoxy; andR² is optionally substituted indan-2-yl.
 2. A compound or salt accordingto claim 1, of Formula III:

wherein: Ar³ is imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl orpyrimidinyl, each of which is substituted with from 0 to 3 substituentsindependently selected from halogen, hydroxy, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₂alkylthio, and —NHC(═O)C₁-C₂alkyl; R⁶ representsfrom 0 to 4 substituents independently selected from halogen, hydroxy,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,C₁-C₂alkylthio, and —NHC(═O) C₁-C₂ alkyl; R¹ is: i)(heteroaryl)C₀-C₄alkyl or (aryl) C₀-C₄alkyl, each of which issubstituted with from 0 to 3 substituents independently selected fromhalogen, hydroxy, nitro, cyano, —COOH, —CONH₂, C₁-C₄ alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkylthio,—NC(═O)C₁-C₂alkyl, mono- and di(C₁-C₂alkyl)amino, C₂-C₃alkanoyloxy,C₁-C₃alkoxycarbonyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, thienyl, andphenyl; or ii) (aryl)C₁-C₄alkyl substituted with from 0 to 5substituents independently chosen from halogen, hydroxy, C₁-C₂ alkyl,C₁-C₂ alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, wherein the arylportion is fused to a 5- to 7-membered saturated or partiallyunsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosenfrom N, O and S, with remaining ring atoms being carbon, and (b) issubstituted with from 0 to 2 substituents independently chosen fromhalogen, C₁-C₄alkyl and C₁-C₄alkoxy; and R² is indan-2-yl which issubstituted with from 0 to 5 substituents independently selected fromhalogen, hydroxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio,—NC(═O)C₁-C₂alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, thienyl, and phenyl.3. A compound according to claim 2, wherein R² is 2-indanyl substitutedwith from 0 to 2 substituents independently selected from halogen, C₁-C₄alkyl, and C₁-C₄ alkoxy.
 4. A compound or salt according to claim 2 ofFormula II, wherein:

Ar¹ is phenyl substituted with from 0 to 4 substituents independentlyselected from halogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂ haloalkoxy, C₁-C₂alkylthio, and —NHC(═O) C₁-C₂ alkyl,and substituted at the 2-position relative to the point of attachmentwith imidazolyl, pyrrolyl, pyrazolyl, oxazoly, thiazolyl, orpyrimidinyl, each of which is substituted with from 0 to 3 substituentsindependently selected from halogen, amino, cyano, hydroxy, C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, mono- anddi-C₁-C₄alkylamino, C₁-C₂alkylthio, and —NHC(═O) C₁-C₂alkyl; Ar² isselected from: i) phenyl, ii) naphthyl, iii) a heterocycle having 1 or 2rings, 3 to 8 atoms in each ring, and 1 to 3 heteroatoms independentlyselected from N, O, and S; and iv) phenyl fused to a 5- to 7-memberedsaturated or partially unsaturated ring having 0, 1, or 2 ring atomsindependently chosen from N, O, and S, with remaining ring atoms beingcarbon; wherein each of i), ii), iii), and iv) is substituted with from0 to 5 substituents independently selected from halogen, hydroxy, —COOH,—CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy,C₁-C₂ alkylthio, and —NHC(═O) C₁-C₂ alkyl; R²is indan-2-yl which issubstituted with from 0 to 3 substituents independently selected fromhalogen, hydroxy, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄alkylthio,—NC(═O)C₁-C₂alkyl, C₁-C₂ haloalkyl, C₁-C₂haloalkoxy, thienyl, andphenyl; and R³ and R⁴ are independently selected from hydrogen, C₁-C₄alkyl, C₂-C₄alkenyl, and C₂-C₄alkynyl.
 5. A compound or salt accordingto claim 2 wherein R² is 2-indanyl, substituted with from 0 to 2substituents independently selected from chloro, fluoro, methyl andmethoxy.
 6. A compound according to claim 2, wherein R² is 2-indanylwhich is substituted with from 0 to 2 substituents independentlyselected from halogen, hydroxy, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.
 7. A compound or salt according to claim 2 ofFormula IV:

wherein Z¹ is carbon or nitrogen; Z², Z³, and each occurrence of Z⁴ areindependently selected from CR⁷, NR⁸, and O such that each O ring atom,if any, is disposed between two CR⁷ groups, p is an integer ranging from1 to 2; R⁶ represents from 0 to 4 substituents independently selectedfrom halogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₂ alkylthio, and —NHC(═O)C₁-C₂ alkyl; R⁷ isindependently selected at each occurrence from hydrogen, halogen,hydroxy, amino, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, mono-anddi-(C₁-C₆alkyl)amino, cyano, nitro, and C₁-C₆alkanoyl; and R⁸ isindependently selected at each occurrence from hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, andC₁-C₆alkanoyl.
 8. A compound or salt according to claim 7 of Formula V:

wherein one of Z² or Z³ is oxygen; and R⁹ represents from 0 to 3substituents independently selected from hydrogen, fluoro, chloro,hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₂haloalkyl, and C₁-C₆haloalkoxy.9. A compound or salt according claim 7 of Formula VI:

wherein Z³ is nitrogen or CR⁹; and R⁹ represents from 0 to 3substituents independently selected from hydrogen, fluoro, chloro,hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₂haloalkyl, and C₁-C₆haloalkoxy.10. A compound or salt according to claim 4 of Formula VII:

wherein Z¹ is carbon or nitrogen; Z², Z³, and each occurrence of Z⁴ areindependently selected from CR⁷, NR⁸, and O such that each O ring atom,if any, is disposed between two CR⁷ groups, p is an integer ranging from1 to 2; R⁶ represents from 0 to 4 substituents independently selectedfrom halogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₂ alkylthio, and —NHC(═O)C₁-C₂ alkyl; R⁷ isindependently selected at each occurrence from hydrogen, halogen,hydroxy, amino, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, mono-anddi-(C₁-C₆alkyl)amino, cyano, nitro, and C₁-C₆alkanoyl; and R⁸ isindependently selected at each occurrence from hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, andC₁-C₆alkanoyl.
 11. A compound or salt according to claim 1 which is:N-Indan-2-yl-N-(3-methyl-benzyl)-2-pyrrol-1-yl-benzamide;N-(indan-2-yl)-N-(3-methylbenzyl)-2-(1H-pyrrol-1-yl)benzamide;N-(indan-2-yl)-N-(4-methylbenzyl)-2-(1H-pyrrol-1-yl)benzamide;N-Indan-2-yl-N-(4-methyl-benzyl)-2-pyrrol-1-yl-benzamide;N-(4-chlorobenzyl)-N-(indan-2-yl)-2-(1H-pyrrol-1-yl)benzamide;N-(indan-2-yl)-2-(1H-pyrrol-1-yl)-N-[4-(trifluoromethyl)benzyl]benzamide;N-(indan-2-yl)-N-(3,5-dimethylbenzyl)-2-(1H-pyrrol-1-yl)benzamide;N-(indan-2-yl)-N-(1-naphthylmethyl)-2-(1H-pyrrol-1-yl)benzamide;N-(indan-2-yl)-N-(2-naphthylmethyl)-2-(1H-pyrrol-1-yl)benzamide; or apharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising at least one compound or salt according to claim1, or a prodrug or hydrate thereof, in combination with aphysiologically acceptable carrier or excipient.
 13. A method fortreating a patient suffering from rheumatoid arthritis, psoriasis, orbronchial asthma comprising administering to the patient an effectiveamount of a compound according to claim
 1. 14. A method for treating apatient suffering from ischemia-reperfusion injury comprisingadministering to the patient an effective amount of a compound accordingto claim
 1. 15. A method for localizing C5a receptors in a tissuesample, comprising: contacting the tissue sample containing C5areceptors with a radiolabeled compound according to claim 1 underconditions that permit binding of the compound to C5a receptors; anddetecting the bound radiolabeled compound by autoradiography orscintillation counting.
 16. A packaged pharmaceutical preparation,comprising: (a) a pharmaceutical composition according to claim 12 in acontainer; and (b) instructions for using the composition to treat apatient suffering from rheumatoid arthritis, psoriasis, or bronchialasthma.
 17. A packaged pharmaceutical preparation (a) a pharmaceuticalcomposition according to claim 12 in a container; and (b) instructionsfor using the composition to treat or ischemia-reperfusion injury.
 18. Apharmaceutical composition according to claim 12, wherein thepharmaceutical composition is formulated as an injectible fluid, anaerosol, a cream, a gel, a pill, a capsule, a syrup, or a transdermalpatch.
 19. A method for treating a patient suffeting from an autoimmunedisorder, comprising administering to the patient an effective amount ofa compound or salt according to claim
 1. 20. A method for treating apatient suffering from an inflammatory disorder, comprisingadministering to the patient an effective amount of a compound or saltaccording to claim 1.